43 results on '"Pauken KE"'
Search Results
2. Longitudinal Intravascular Antibody Labeling Identified Regulatory T Cell Recruitment as a Therapeutic Target in a Mouse Model of Lung Cancer.
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Shanahan SL, Kunder N, Inaku C, Hagan NB, Gibbons G, Mathey-Andrews N, Anandappa G, Soares S, Pauken KE, Jacks T, and Schenkel JM
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- Animals, Mice, Mice, Inbred C57BL, Tumor Microenvironment immunology, Adenocarcinoma immunology, Cell Line, Tumor, T-Lymphocytes, Regulatory immunology, Lung Neoplasms immunology, Lung Neoplasms pathology, Disease Models, Animal, Cell Movement immunology
- Abstract
Anticancer immunity is predicated on leukocyte migration into tumors. Once recruited, leukocytes undergo substantial reprogramming to adapt to the tumor microenvironment. A major challenge in the field is distinguishing recently recruited from resident leukocytes in tumors. In this study, we developed an intravascular Ab technique to label circulating mouse leukocytes before they migrate to tissues, providing unprecedented insight into the kinetics of recruitment. This approach unveiled the substantial role of leukocyte migration in tumor progression using a preclinical mouse model of lung adenocarcinoma. Regulatory T cells (Tregs), critical mediators of immunosuppression, were continuously and rapidly recruited into tumors throughout cancer progression. Moreover, leukocyte trafficking depended on the integrins CD11a/CD49d, and CD11a/CD49d blockade led to significant tumor burden reduction in mice. Importantly, preventing circulating Treg recruitment through depletion or sequestration in lymph nodes was sufficient to decrease tumor burden, indicating that Treg migration was crucial for suppressing antitumor immunity. These findings underscore the dynamic nature of the immune compartment within mouse lung tumors and demonstrate the relevance of a temporal map of leukocyte recruitment into tumors, thereby advancing our understanding of leukocyte migration in the context of tumor development., (Copyright © 2024 by The American Association of Immunologists, Inc.)
- Published
- 2024
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3. In vivo antibody labeling route and fluorophore dictate labeling efficiency, sensitivity, and longevity.
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Hagan NB, Inaku C, Kunder N, White T, Iraguha T, Meyer A, Pauken KE, and Schenkel JM
- Abstract
Leukocytes migrate through the blood and extravasate into organs to surveil the host for infection or cancer. Recently, we demonstrated that intravenous (IV) anti-CD45.2 antibody labeling allowed for precise tracking of leukocyte migration. However, the narrow labeling window can make this approach challenging for tracking rare migration events. Here, we show that altering antibody administration route and fluorophore can significantly extend the antibody active labeling time. We found that while both IV and intraperitoneal (IP) anti-CD45.2 antibody labeled circulating leukocytes after injection, they had different kinetic properties that impacted labeling time and intensity. Quantification of circulating antibody revealed that while unbound IV anti-CD45.2 antibody rapidly decreased, unbound IP anti-CD45.2 antibody increased over one hour. Using in vitro and in vivo serial dilution assays, we found that Alexa Fluor 647 (AF647) and Brilliant Blue 700 (BB700) dyes had the greatest labeling sensitivity compared to other fluorophores. However, IP antibody injection with anti-CD45.2 BB700, but not AF647, resulted in continuous blood leukocyte labeling for over 6 hours. Finally, we leveraged IP anti-CD45.2 BB700 antibody to track slower migrating leukocytes into tumors. We found that IP anti-CD45.2 antibody injection allowed for the identification of ~seven times as many tumor-specific CD8
+ T cells that had recently migrated from blood into tumors. Our results demonstrate how different injection routes and fluorophores affect anti-CD45.2 antibody leukocyte labeling and highlight the utility of this approach for defining leukocyte migration in the context of homeostasis and cancer.- Published
- 2024
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4. Neoantigen Cancer Vaccines and Different Immune Checkpoint Therapies Each Utilize Both Converging and Distinct Mechanisms that in Combination Enable Synergistic Therapeutic Efficacy.
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Keshari S, Shavkunov AS, Miao Q, Saha A, Williams CD, Highsmith AM, Pineda JE, Alspach E, Hu KH, Pauken KE, Chen K, and Gubin MM
- Abstract
The goal of therapeutic cancer vaccines and immune checkpoint therapy (ICT) is to eliminate cancer by expanding and/or sustaining T cells with anti-tumor capabilities. However, whether cancer vaccines and ICT enhance anti-tumor immunity by distinct or overlapping mechanisms remains unclear. Here, we compared effective therapeutic tumor-specific mutant neoantigen (NeoAg) cancer vaccines with anti-CTLA-4 and/or anti-PD-1 ICT in preclinical models. Both NeoAg vaccines and ICT induce expansion of intratumoral NeoAg-specific CD8 T cells, though the degree of expansion and acquisition of effector activity was much more substantial following NeoAg vaccination. Further, we found that NeoAg vaccines are particularly adept at inducing proliferating and stem-like NeoAg-specific CD8 T cells. Single cell T cell receptor (TCR) sequencing revealed that TCR clonotype expansion and diversity of NeoAg-specific CD8 T cells relates to their phenotype and functional state associated with specific immunotherapies employed. Effective NeoAg vaccines and ICT required both CD8 and CD4 T cells. While NeoAg vaccines and anti-PD-1 affected the CD4 T cell compartment, it was to less of an extent than observed with anti-CTLA-4, which notably induced ICOS
+ Bhlhe40+ Th1-like CD4 T cells and, when combined with anti-PD-1, a small subset of Th2-like CD4 T cells. Although effective NeoAg vaccines or ICT expanded intratumoral M1-like iNOS+ macrophages, NeoAg vaccines expanded rather than suppressed (as observed with ICT) M2-like CX3CR1+ CD206+ macrophages, associated with the vaccine adjuvant. Further, combining NeoAg vaccination with ICT induced superior efficacy compared to either therapy in isolation, highlighting the utility of combining these modalities to eliminate cancer., Competing Interests: Declaration of interests M.M. Gubin reports a personal honorarium of $1000.00 USD per year from Springer Nature Ltd for his role as an Associate Editor for the journal Nature Precision Oncology. No disclosures were reported by the other authors.- Published
- 2024
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5. Formate Supplementation Enhances Antitumor CD8+ T-cell Fitness and Efficacy of PD-1 Blockade.
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Rowe JH, Elia I, Shahid O, Gaudiano EF, Sifnugel NE, Johnson S, Reynolds AG, Fung ME, Joshi S, LaFleur MW, Park JS, Pauken KE, Rabinowitz JD, Freeman GJ, Haigis MC, and Sharpe AH
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- Humans, CD8-Positive T-Lymphocytes metabolism, Formates, Dietary Supplements, Tumor Microenvironment, Programmed Cell Death 1 Receptor metabolism, Neoplasms genetics
- Abstract
The tumor microenvironment (TME) restricts antitumor CD8+ T-cell function and immunotherapy responses. Cancer cells compromise the metabolic fitness of CD8+ T cells within the TME, but the mechanisms are largely unknown. Here we demonstrate that one-carbon (1C) metabolism is enhanced in T cells in an antigen-specific manner. Therapeutic supplementation of 1C metabolism using formate enhances CD8+ T-cell fitness and antitumor efficacy of PD-1 blockade in B16-OVA tumors. Formate supplementation drives transcriptional alterations in CD8+ T-cell metabolism and increases gene signatures for cellular proliferation and activation. Combined formate and anti-PD-1 therapy increases tumor-infiltrating CD8+ T cells, which are essential for enhanced tumor control. Our data demonstrate that formate provides metabolic support to CD8+ T cells reinvigorated by anti-PD-1 to overcome a metabolic vulnerability in 1C metabolism in the TME to further improve T-cell function., Significance: This study identifies that deficiencies in 1C metabolism limit the efficacy of PD-1 blockade in B16-OVA tumors. Supplementing 1C metabolism with formate during anti-PD-1 therapy enhances CD8+ T-cell fitness in the TME and CD8+ T-cell-mediated tumor clearance. These findings demonstrate that formate supplementation can enhance exhausted CD8+ T-cell function. See related commentary by Lin et al., p. 2507. This article is featured in Selected Articles from This Issue, p. 2489., (©2023 American Association for Cancer Research.)
- Published
- 2023
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6. Localization, tissue biology and T cell state - implications for cancer immunotherapy.
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Schenkel JM and Pauken KE
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- Humans, Immunologic Memory, Immunotherapy, Biology, Tumor Microenvironment, CD8-Positive T-Lymphocytes, Neoplasms
- Abstract
Tissue localization is a critical determinant of T cell immunity. CD8
+ T cells are contact-dependent killers, which requires them to physically be within the tissue of interest to kill peptide-MHC class I-bearing target cells. Following their migration and extravasation into tissues, T cells receive many extrinsic cues from the local microenvironment, and these signals shape T cell differentiation, fate and function. Because major organ systems are variable in their functions and compositions, they apply disparate pressures on T cells to adapt to the local microenvironment. Additional complexity arises in the context of malignant lesions (either primary or metastatic), and this has made understanding the factors that dictate T cell function and longevity in tumours challenging. Moreover, T cell differentiation state influences how cues from the microenvironment are interpreted by tissue-infiltrating T cells, highlighting the importance of T cell state in the context of tissue biology. Here, we review the intertwined nature of T cell differentiation state, location, survival and function, and explain how dysfunctional T cell populations can adopt features of tissue-resident memory T cells to persist in tumours. Finally, we discuss how these factors have shaped responses to cancer immunotherapy., (© 2023. Springer Nature Limited.)- Published
- 2023
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7. Single-cell profiling reveals unique features of diabetogenic T cells in anti-PD-1-induced type 1 diabetes mice.
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Collier JL, Pauken KE, Lee CAA, Patterson DG, Markson SC, Conway TS, Fung ME, France JA, Mucciarone KN, Lian CG, Murphy GF, and Sharpe AH
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- Animals, Mice, Mice, Inbred NOD, Pancreas, Forkhead Transcription Factors, Receptors, Antigen, T-Cell, Diabetes Mellitus, Type 1
- Abstract
Immune-related adverse events (irAEs) are a notable complication of PD-1 cancer immunotherapy. A better understanding of how these iatrogenic diseases compare with naturally arising autoimmune diseases is needed for treatment and monitoring of irAEs. We identified differences in anti-PD-1-induced type 1 diabetes (T1D) and spontaneous T1D in non-obese diabetic (NOD) mice by performing single-cell RNA-seq and TCR-seq on T cells from the pancreas, pancreas-draining lymph node (pLN), and blood of mice with PD-1-induced T1D or spontaneous T1D. In the pancreas, anti-PD-1 resulted in expansion of terminally exhausted/effector-like CD8+ T cells, an increase in T-bethi CD4+FoxP3- T cells, and a decrease in memory CD4+FoxP3- and CD8+ T cells in contrast to spontaneous T1D. Notably, anti-PD-1 caused increased TCR sharing between the pancreas and the periphery. Moreover, T cells in the blood of anti-PD-1-treated mice expressed markers that differed from spontaneous T1D, suggesting that the blood may provide a window to monitor irAEs rather than relying exclusively on the autoimmune target organ., (© 2023 Collier et al.)
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- 2023
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8. Microenvironmental Landscape of Human Melanoma Brain Metastases in Response to Immune Checkpoint Inhibition.
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Alvarez-Breckenridge C, Markson SC, Stocking JH, Nayyar N, Lastrapes M, Strickland MR, Kim AE, de Sauvage M, Dahal A, Larson JM, Mora JL, Navia AW, Klein RH, Kuter BM, Gill CM, Bertalan M, Shaw B, Kaplan A, Subramanian M, Jain A, Kumar S, Danish H, White M, Shahid O, Pauken KE, Miller BC, Frederick DT, Hebert C, Shaw M, Martinez-Lage M, Frosch M, Wang N, Gerstner E, Nahed BV, Curry WT, Carter B, Cahill DP, Boland GM, Izar B, Davies MA, Sharpe AH, Suvà ML, Sullivan RJ, Brastianos PK, and Carter SL
- Subjects
- Humans, Immune Checkpoint Inhibitors, Tumor Microenvironment, Brain Neoplasms, Melanoma
- Abstract
Melanoma-derived brain metastases (MBM) represent an unmet clinical need because central nervous system progression is frequently an end stage of the disease. Immune checkpoint inhibitors (ICI) provide a clinical opportunity against MBM; however, the MBM tumor microenvironment (TME) has not been fully elucidated in the context of ICI. To dissect unique elements of the MBM TME and correlates of MBM response to ICI, we collected 32 fresh MBM and performed single-cell RNA sequencing of the MBM TME and T-cell receptor clonotyping on T cells from MBM and matched blood and extracranial lesions. We observed myeloid phenotypic heterogeneity in the MBM TME, most notably multiple distinct neutrophil states, including an IL8-expressing population that correlated with malignant cell epithelial-to-mesenchymal transition. In addition, we observed significant relationships between intracranial T-cell phenotypes and the distribution of T-cell clonotypes intracranially and peripherally. We found that the phenotype, clonotype, and overall number of MBM-infiltrating T cells were associated with response to ICI, suggesting that ICI-responsive MBMs interact with peripheral blood in a manner similar to extracranial lesions. These data identify unique features of the MBM TME that may represent potential targets to improve clinical outcomes for patients with MBM., (©2022 American Association for Cancer Research.)
- Published
- 2022
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9. Repertoire analyses reveal T cell antigen receptor sequence features that influence T cell fate.
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Lagattuta KA, Kang JB, Nathan A, Pauken KE, Jonsson AH, Rao DA, Sharpe AH, Ishigaki K, and Raychaudhuri S
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- Cell Lineage, Complementarity Determining Regions genetics, Peptides, T-Lymphocytes, Regulatory, Receptors, Antigen, T-Cell, Receptors, Antigen, T-Cell, alpha-beta genetics
- Abstract
T cells acquire a regulatory phenotype when their T cell antigen receptors (TCRs) experience an intermediate- to high-affinity interaction with a self-peptide presented via the major histocompatibility complex (MHC). Using TCRβ sequences from flow-sorted human cells, we identified TCR features that promote regulatory T cell (T
reg ) fate. From these results, we developed a scoring system to quantify TCR-intrinsic regulatory potential (TiRP). When applied to the tumor microenvironment, TiRP scoring helped to explain why only some T cell clones maintained the conventional T cell (Tconv ) phenotype through expansion. To elucidate drivers of these predictive TCR features, we then examined the two elements of the Treg TCR ligand separately: the self-peptide and the human MHC class II molecule. These analyses revealed that hydrophobicity in the third complementarity-determining region (CDR3β) of the TCR promotes reactivity to self-peptides, while TCR variable gene (TRBV gene) usage shapes the TCR's general propensity for human MHC class II-restricted activation., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)- Published
- 2022
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10. TCR-sequencing in cancer and autoimmunity: barcodes and beyond.
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Pauken KE, Lagattuta KA, Lu BY, Lucca LE, Daud AI, Hafler DA, Kluger HM, Raychaudhuri S, and Sharpe AH
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- Humans, Receptors, Antigen, T-Cell genetics, T-Lymphocytes, Autoimmunity genetics, Neoplasms genetics
- Abstract
The T cell receptor (TCR) endows T cells with antigen specificity and is central to nearly all aspects of T cell function. Each naïve T cell has a unique TCR sequence that is stably maintained during cell division. In this way, the TCR serves as a molecular barcode that tracks processes such as migration, differentiation, and proliferation of T cells. Recent technological advances have enabled sequencing of the TCR from single cells alongside deep molecular phenotypes on an unprecedented scale. In this review, we discuss strengths and limitations of TCR sequences as molecular barcodes and their application to study immune responses following Programmed Death-1 (PD-1) blockade in cancer. Additionally, we consider applications of TCR data beyond use as a barcode., Competing Interests: Declaration of interests No interests are declared., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
- Published
- 2022
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11. Conventional type I dendritic cells maintain a reservoir of proliferative tumor-antigen specific TCF-1 + CD8 + T cells in tumor-draining lymph nodes.
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Schenkel JM, Herbst RH, Canner D, Li A, Hillman M, Shanahan SL, Gibbons G, Smith OC, Kim JY, Westcott P, Hwang WL, Freed-Pastor WA, Eng G, Cuoco MS, Rogers P, Park JK, Burger ML, Rozenblatt-Rosen O, Cong L, Pauken KE, Regev A, and Jacks T
- Subjects
- Animals, Mice, T-Lymphocyte Subsets immunology, Adenocarcinoma of Lung immunology, CD8-Positive T-Lymphocytes immunology, Dendritic Cells immunology, Lung Neoplasms immunology, Lymph Nodes immunology, T Cell Transcription Factor 1 immunology
- Abstract
In tumors, a subset of CD8
+ T cells expressing the transcription factor TCF-1 drives the response to immune checkpoint blockade. We examined the mechanisms that maintain these cells in an autochthonous model of lung adenocarcinoma. Longitudinal sampling and single-cell sequencing of tumor-antigen specific TCF-1+ CD8+ T cells revealed that while intratumoral TCF-1+ CD8+ T cells acquired dysfunctional features and decreased in number as tumors progressed, TCF-1+ CD8+ T cell frequency in the tumor draining LN (dLN) remained stable. Two discrete intratumoral TCF-1+ CD8+ T cell subsets developed over time-a proliferative SlamF6+ subset and a non-cycling SlamF6- subset. Blocking dLN egress decreased the frequency of intratumoral SlamF6+ TCF-1+ CD8+ T cells. Conventional type I dendritic cell (cDC1) in dLN decreased in number with tumor progression, and Flt3L+anti-CD40 treatment recovered SlamF6+ T cell frequencies and decreased tumor burden. Thus, cDC1s in tumor dLN maintain a reservoir of TCF-1+ CD8+ T cells and their decrease contributes to failed anti-tumor immunity., Competing Interests: Declaration of interests T.J. is a member of the Board of Directors of Amgen and Thermo Fisher Scientific. He is also a co-founder of Dragonfly Therapeutics and T2 Biosystems. T.J. serves on the Scientific Advisory Board of Dragonfly Therapeutics, SQZ Biotech, and Skyhawk Therapeutics. He is the President of Break Through Cancer. None of these affiliations represent a conflict of interest with respect to the design or execution of this study or interpretation of data presented in this manuscript. T.J. laboratory currently also receives funding from the Johnson & Johnson Lung Cancer Initiative and The Lustgarten Foundation for Pancreatic Cancer Research, but this funding did not support the research described in this manuscript. A.R. is a co-founder and equity holder of Celsius Therapeutics, an equity holder in Immunitas, and was an SAB member of ThermoFisher Scientific, Syros Pharmaceuticals, Neogene Therapeutics and Asimov until July 31, 2020. From August 1, 2020, A.R. is an employee of Genentech., (Copyright © 2021 Elsevier Inc. All rights reserved.)- Published
- 2021
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12. Not-so-opposite ends of the spectrum: CD8 + T cell dysfunction across chronic infection, cancer and autoimmunity.
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Collier JL, Weiss SA, Pauken KE, Sen DR, and Sharpe AH
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- Animals, Autoimmune Diseases genetics, Autoimmune Diseases metabolism, B7-H1 Antigen immunology, B7-H1 Antigen metabolism, CD8-Positive T-Lymphocytes drug effects, CD8-Positive T-Lymphocytes metabolism, Chronic Disease, Communicable Diseases genetics, Communicable Diseases metabolism, Cytokines immunology, Cytokines metabolism, Epigenesis, Genetic, Humans, Immune Checkpoint Inhibitors therapeutic use, Lymphocytes, Tumor-Infiltrating drug effects, Lymphocytes, Tumor-Infiltrating metabolism, Neoplasms drug therapy, Neoplasms genetics, Neoplasms metabolism, Phenotype, Programmed Cell Death 1 Receptor immunology, Programmed Cell Death 1 Receptor metabolism, Receptors, Antigen, T-Cell immunology, Receptors, Antigen, T-Cell metabolism, Signal Transduction, Autoimmune Diseases immunology, Autoimmunity, CD8-Positive T-Lymphocytes immunology, Communicable Diseases immunology, Lymphocytes, Tumor-Infiltrating immunology, Neoplasms immunology
- Abstract
CD8
+ T cells are critical mediators of cytotoxic effector function in infection, cancer and autoimmunity. In cancer and chronic viral infection, CD8+ T cells undergo a progressive loss of cytokine production and cytotoxicity, a state termed T cell exhaustion. In autoimmunity, autoreactive CD8+ T cells retain the capacity to effectively mediate the destruction of host tissues. Although the clinical outcome differs in each context, CD8+ T cells are chronically exposed to antigen in all three. These chronically stimulated CD8+ T cells share some common phenotypic features, as well as transcriptional and epigenetic programming, across disease contexts. A better understanding of these CD8+ T cell states may reveal novel strategies to augment clearance of chronic viral infection and cancer and to mitigate self-reactivity leading to tissue damage in autoimmunity.- Published
- 2021
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13. Single-cell analyses identify circulating anti-tumor CD8 T cells and markers for their enrichment.
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Pauken KE, Shahid O, Lagattuta KA, Mahuron KM, Luber JM, Lowe MM, Huang L, Delaney C, Long JM, Fung ME, Newcomer K, Tsai KK, Chow M, Guinn S, Kuchroo JR, Burke KP, Schenkel JM, Rosenblum MD, Daud AI, Sharpe AH, and Singer M
- Subjects
- Adenocarcinoma pathology, Animals, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Cell Line, Tumor, Colonic Neoplasms pathology, Female, Humans, Mice, Mice, Inbred C57BL, Programmed Cell Death 1 Receptor genetics, Programmed Cell Death 1 Receptor metabolism, Receptors, Antigen, T-Cell genetics, Receptors, Antigen, T-Cell metabolism, Transcriptome, Adenocarcinoma immunology, CD8-Positive T-Lymphocytes immunology, Colonic Neoplasms immunology, Melanoma blood, Melanoma immunology, Single-Cell Analysis methods, Skin Neoplasms blood, Skin Neoplasms immunology
- Abstract
The ability to monitor anti-tumor CD8+ T cell responses in the blood has tremendous therapeutic potential. Here, we used paired single-cell RNA and TCR sequencing to detect and characterize "tumor-matching" (TM) CD8+ T cells in the blood of mice with MC38 tumors or melanoma patients using the TCR as a molecular barcode. TM cells showed increased activation compared with nonmatching T cells in blood and were less exhausted than matching cells in tumors. Importantly, PD-1, which has been used to identify putative circulating anti-tumor CD8+ T cells, showed poor sensitivity for identifying TM cells. By leveraging the transcriptome, we identified candidate cell surface markers for TM cells in mice and patients and validated NKG2D, CD39, and CX3CR1 in mice. These data show that the TCR can be used to identify tumor-relevant cells for characterization, reveal unique transcriptional properties of TM cells, and develop marker panels for tracking and analysis of these cells., Competing Interests: Disclosures: K. Tsai reported personal fees from Regeneron, grants from Array/Pfizer, grants from Replimune, and grants from Oncosec outside the submitted work. M. Rosenblum reported other from TRex Bio and other from Sitryx Bio outside the submitted work. A. Daud reported grants from Merck, grants from BMS, other from Trex, grants from Pfizer, grants from Incyte, grants from Xencor, grants from Roche, and grants from Novartis during the conduct of the study as well as grants from Oncosec outside the submitted work. A. Sharpe reported grants from NIH R01 CA229851, grants from NIH U54 CA224088, grants from NIH P01 56299, and grants from NIH P01 39671 during the conduct of the study; personal fees from Surface Oncology, personal fees from Sqz Biotech, personal fees from Selecta, personal fees from Monopteros, personal fees from Elstar, personal fees from Elpiscience, grants from Novartis, grants from Roche, grants from Merck, grants from Ipsen, grants from UCB, and grants from Quark Ventures outside the submitted work. In addition, A. Sharpe had a patent number 7,432,059 with royalties paid (Roche, Merck, Bristol-Myers-Squibb, EMD-Serono, Boehringer-Ingelheim, AstraZeneca, Leica, Mayo Clinic, Dako and Novartis), a patent number 7,722,868 with royalties paid (Roche, Merck, Bristol-Myers-Squibb, EMD-Serono, Boehringer-Ingelheim, AstraZeneca, Leica, Mayo Clinic, Dako and Novartis), a patent number 8,652,465 licensed (Roche), a patent number 9,457,080 licensed (Roche), a patent number 9,683,048 licensed (Novartis), a patent number 9,815,898 licensed (Novartis), a patent number 9,845,356 licensed (Novartis), a patent number 10,202,454 licensed (Novartis), a patent number 10,457,733 licensed (Novartis), a patent number 9,580,684 issued (none), a patent number 9,988,452 issued (none), and a patent number 10,370,446 issued (none); A. Sharpe is on the scientific advisory boards for the Massachusetts General Cancer Center, Program in Cellular and Molecular Medicine at Boston Children's Hospital, and the Human Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center and is a scientific editor for the Journal of Experimental Medicine. M. Singer reported personal fees from Guardant Health outside the submitted work. No other disclosures were reported., (© 2021 Pauken et al.)
- Published
- 2021
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14. Epitope spreading toward wild-type melanocyte-lineage antigens rescues suboptimal immune checkpoint blockade responses.
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Lo JA, Kawakubo M, Juneja VR, Su MY, Erlich TH, LaFleur MW, Kemeny LV, Rashid M, Malehmir M, Rabi SA, Raghavan R, Allouche J, Kasumova G, Frederick DT, Pauken KE, Weng QY, Pereira da Silva M, Xu Y, van der Sande AAJ, Silkworth W, Roider E, Browne EP, Lieb DJ, Wang B, Garraway LA, Wu CJ, Flaherty KT, Brinckerhoff CE, Mullins DW, Adams DJ, Hacohen N, Hoang MP, Boland GM, Freeman GJ, Sharpe AH, Manstein D, and Fisher DE
- Subjects
- Animals, Antigens, Neoplasm, Epitopes, Humans, Melanocytes, Mice, Immune Checkpoint Inhibitors, Melanoma therapy
- Abstract
Although immune checkpoint inhibitors (ICIs), such as anti-programmed cell death protein-1 (PD-1), can deliver durable antitumor effects, most patients with cancer fail to respond. Recent studies suggest that ICI efficacy correlates with a higher load of tumor-specific neoantigens and development of vitiligo in patients with melanoma. Here, we report that patients with low melanoma neoantigen burdens who responded to ICI had tumors with higher expression of pigmentation-related genes. Moreover, expansion of peripheral blood CD8
+ T cell populations specific for melanocyte antigens was observed only in patients who responded to anti-PD-1 therapy, suggesting that ICI can promote breakdown of tolerance toward tumor-lineage self-antigens. In a mouse model of poorly immunogenic melanomas, spreading of epitope recognition toward wild-type melanocyte antigens was associated with markedly improved anti-PD-1 efficacy in two independent approaches: introduction of neoantigens by ultraviolet (UV) B radiation mutagenesis or the therapeutic combination of ablative fractional photothermolysis plus imiquimod. Complete responses against UV mutation-bearing tumors after anti-PD-1 resulted in protection from subsequent engraftment of melanomas lacking any shared neoantigens, as well as pancreatic adenocarcinomas forcibly overexpressing melanocyte-lineage antigens. Our data demonstrate that somatic mutations are sufficient to provoke strong antitumor responses after checkpoint blockade, but long-term responses are not restricted to these putative neoantigens. Epitope spreading toward T cell recognition of wild-type tumor-lineage self-antigens represents a common pathway for successful response to ICI, which can be evoked in neoantigen-deficient tumors by combination therapy with ablative fractional photothermolysis and imiquimod., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)- Published
- 2021
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15. Emerging concepts in PD-1 checkpoint biology.
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Pauken KE, Torchia JA, Chaudhri A, Sharpe AH, and Freeman GJ
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- Humans, Killer Cells, Natural, Lymphocyte Activation, Immune Checkpoint Inhibitors therapeutic use, Neoplasms therapy, Programmed Cell Death 1 Receptor antagonists & inhibitors
- Abstract
The PD-1 pathway is a cornerstone in immune regulation. While the PD-1 pathway has received considerable attention for its role in contributing to the maintenance of T cell exhaustion in chronic infection and cancer, the PD-1 pathway plays diverse roles in regulating host immunity beyond T cell exhaustion. Here, we discuss emerging concepts in the PD-1 pathway, including (1) the impact of PD-1 inhibitors on diverse T cell differentiation states including effector and memory T cell development during acute infection, as well as T cell exhaustion during chronic infection and cancer, (2) the role of PD-1 in regulating Treg cells, NK cells, and ILCs, and (3) the functions of PD-L1/B7-1 and PD-L2/RGMb/neogenin interactions. We then discuss the emerging use of neoadjuvant PD-1 blockade in the treatment of early-stage cancers and how the timing of PD-1 blockade may improve clinical outcomes. The diverse binding partners of PD-1 and its associated ligands, broad expression patterns of the receptors and ligands, differential impact of PD-1 modulation on cells depending on location and state of differentiation, and timing of PD-1 blockade add additional layers of complexity to the PD-1 pathway, and are important considerations for improving the efficacy and safety of PD-1 pathway therapeutics., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2021
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16. Inhibitory signaling sustains a distinct early memory CD8 + T cell precursor that is resistant to DNA damage.
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Johnnidis JB, Muroyama Y, Ngiow SF, Chen Z, Manne S, Cai Z, Song S, Platt JM, Schenkel JM, Abdel-Hakeem M, Beltra JC, Greenplate AR, Ali MA, Nzingha K, Giles JR, Harly C, Attanasio J, Pauken KE, Bengsch B, Paley MA, Tomov VT, Kurachi M, Vignali DAA, Sharpe AH, Reiner SL, Bhandoola A, Johnson FB, and Wherry EJ
- Subjects
- Animals, Antigens, CD genetics, CD8-Positive T-Lymphocytes metabolism, Cell Differentiation genetics, Cell Differentiation immunology, DNA Damage immunology, Disease Models, Animal, Female, Hepatocyte Nuclear Factor 1-alpha metabolism, Humans, Immunologic Memory genetics, Listeria monocytogenes immunology, Listeriosis microbiology, Lymphocyte Activation, Lymphocytic Choriomeningitis virology, Lymphocytic choriomeningitis virus immunology, Male, Memory T Cells metabolism, Mice, Mice, Knockout, Precursor Cells, T-Lymphoid metabolism, Programmed Cell Death 1 Receptor genetics, Lymphocyte Activation Gene 3 Protein, CD8-Positive T-Lymphocytes immunology, Listeriosis immunology, Lymphocytic Choriomeningitis immunology, Memory T Cells immunology, Precursor Cells, T-Lymphoid immunology
- Abstract
The developmental origins of memory T cells remain incompletely understood. During the expansion phase of acute viral infection, we identified a distinct subset of virus-specific CD8
+ T cells that possessed distinct characteristics including expression of CD62L, T cell factor 1 (TCF-1), and Eomesodermin; relative quiescence; expression of activation markers; and features of limited effector differentiation. These cells were a quantitatively minor subpopulation of the TCF-1+ pool and exhibited self-renewal, heightened DNA damage surveillance activity, and preferential long-term recall capacity. Despite features of memory and somewhat restrained proliferation during the expansion phase, this subset displayed evidence of stronger TCR signaling than other responding CD8+ T cells, coupled with elevated expression of multiple inhibitory receptors including programmed cell death 1 (PD-1), lymphocyte activating gene 3 (LAG-3), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), CD5, and CD160. Genetic ablation of PD-1 and LAG-3 compromised the formation of this CD62Lhi TCF-1+ subset and subsequent CD8+ T cell memory. Although central memory phenotype CD8+ T cells were formed in the absence of these cells, subsequent memory CD8+ T cell recall responses were compromised. Together, these results identify an important link between genome integrity maintenance and CD8+ T cell memory. Moreover, the data indicate a role for inhibitory receptors in preserving key memory CD8+ T cell precursors during initial activation and differentiation. Identification of this rare subpopulation within the memory CD8+ T cell precursor pool may help reconcile models of the developmental origin of long-term CD8+ T cell memory., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)- Published
- 2021
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17. A bilateral tumor model identifies transcriptional programs associated with patient response to immune checkpoint blockade.
- Author
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Chen IX, Newcomer K, Pauken KE, Juneja VR, Naxerova K, Wu MW, Pinter M, Sen DR, Singer M, Sharpe AH, and Jain RK
- Subjects
- Animals, Biomarkers, Tumor immunology, CD8-Positive T-Lymphocytes immunology, Female, Gene Expression Regulation, Neoplastic immunology, Humans, Mice, Mice, Inbred C57BL, Programmed Cell Death 1 Receptor antagonists & inhibitors, Programmed Cell Death 1 Receptor immunology, Transcriptome immunology, Breast Neoplasms immunology, Breast Neoplasms therapy, Immunotherapy, Mammary Neoplasms, Experimental immunology, Mammary Neoplasms, Experimental therapy, Tumor Microenvironment immunology
- Abstract
Immune checkpoint blockade (ICB) is efficacious in many diverse cancer types, but not all patients respond. It is important to understand the mechanisms driving resistance to these treatments and to identify predictive biomarkers of response to provide best treatment options for all patients. Here we introduce a resection and response-assessment approach for studying the tumor microenvironment before or shortly after treatment initiation to identify predictive biomarkers differentiating responders from nonresponders. Our approach builds on a bilateral tumor implantation technique in a murine metastatic breast cancer model (E0771) coupled with anti-PD-1 therapy. Using our model, we show that tumors from mice responding to ICB therapy had significantly higher CD8
+ T cells and fewer Gr1+ CD11b+ myeloid-derived suppressor cells (MDSCs) at early time points following therapy initiation. RNA sequencing on the intratumoral CD8+ T cells identified the presence of T cell exhaustion pathways in nonresponding tumors and T cell activation in responding tumors. Strikingly, we showed that our derived response and resistance signatures significantly segregate patients by survival and associate with patient response to ICB. Furthermore, we identified decreased expression of CXCR3 in nonresponding mice and showed that tumors grown in Cxcr3-/- mice had an elevated resistance rate to anti-PD-1 treatment. Our findings suggest that the resection and response tumor model can be used to identify response and resistance biomarkers to ICB therapy and guide the use of combination therapy to further boost the antitumor efficacy of ICB., Competing Interests: Competing interest statement: R.K.J. received an honorarium from Amgen; consultant fees from Merck, Pfizer, SPARC, and SynDevRx; owns equity in Enlight and SynDevRx; and serves on the scientific advisory board of Accurius Therapeutics and boards of trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund, and Tekla World Healthcare Fund. Neither any reagent nor any funding from these organizations was used in this study. A.H.S. has patents on the PD-1 pathway licensed by Roche/Genentech and Novartis, consults for Novartis, is on the scientific advisory boards for Surface Oncology, Sqz Biotech, Elstar Therapeutics, Elpiscience, Selecta, and Monopteros, and has research funding from Merck, Novartis, Roche, and Quark Ventures. R.K.J. and D.A.T. are co-authors on a 2020 Cold Spring Harbor Laboratory meeting report., (Copyright © 2020 the Author(s). Published by PNAS.)- Published
- 2020
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18. The PD-1 Pathway Regulates Development and Function of Memory CD8 + T Cells following Respiratory Viral Infection.
- Author
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Pauken KE, Godec J, Odorizzi PM, Brown KE, Yates KB, Ngiow SF, Burke KP, Maleri S, Grande SM, Francisco LM, Ali MA, Imam S, Freeman GJ, Haining WN, Wherry EJ, and Sharpe AH
- Subjects
- Administration, Intranasal, Animals, Cell Death immunology, Cell Differentiation immunology, Cell Proliferation, Mice, Inbred C57BL, Orthomyxoviridae Infections pathology, Species Specificity, CD8-Positive T-Lymphocytes immunology, Immunologic Memory, Influenza A Virus, H3N2 Subtype physiology, Orthomyxoviridae Infections immunology, Orthomyxoviridae Infections virology, Programmed Cell Death 1 Receptor metabolism, Signal Transduction
- Abstract
The PD-1 pathway regulates dysfunctional T cells in chronic infection and cancer, but the role of this pathway during acute infection remains less clear. Here, we demonstrate that PD-1 signals are needed for optimal memory. Mice deficient in the PD-1 pathway exhibit impaired CD8
+ T cell memory following acute influenza infection, including reduced virus-specific CD8+ T cell numbers and compromised recall responses. PD-1 blockade during priming leads to similar differences early post-infection but without the defect in memory formation, suggesting that timing and/or duration of PD-1 blockade could be tailored to modulate host responses. Our studies reveal a role for PD-1 as an integrator of CD8+ T cell signals that promotes CD8+ T cell memory formation and suggest PD-1 continues to fine-tune CD8+ T cells after they migrate into non-lymphoid tissues. These findings have important implications for PD-1-based immunotherapy, in which PD-1 inhibition may influence memory responses in patients., Competing Interests: Declaration of Interests A.H.S. and G.J.F. have patents/pending royalties on the PD-1 pathway from Roche, Merck, Bristol-Myers-Squibb, EMD-Serono, Boehringer-Ingelheim, AstraZeneca, Dako, and Novartis. G.J.F. has equity in Nextpoint, Triursus, and Xios. G.J.F. has served on advisory boards for Roche, Bristol-Myers-Squibb, Xios, and Origimed. A.H.S. is on advisory boards for Surface Oncology, Elstar, SQZ Biotechnologies, Selecta, Elpiscience, and Monopteros and has research funding from Novartis, Roche, Ipsen, Quark, and Merck. E.J.W. receives honoraria, consulting fees, and/or research support from BMS, Celgene, Dynavax, Eli Lilly, Elstar, Merck, MedImmune, Pieris, Roche, Surface Oncology, and KyMab. E.J.W. is a founder of Arsenal Biosciences. E.J.W. has a patent licensing agreement for the PD-1 pathway licensed by Genentech/Roche. W.N.H. is a founder of and equity holder at Arsenal Biosciences, equity holder at Tango therapeutics, and employee of Merck and Co., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2020
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19. Adverse Events Following Cancer Immunotherapy: Obstacles and Opportunities.
- Author
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Pauken KE, Dougan M, Rose NR, Lichtman AH, and Sharpe AH
- Subjects
- Animals, Antineoplastic Agents, Immunological administration & dosage, Antineoplastic Agents, Immunological therapeutic use, Autoimmunity, Biomarkers, Tumor, Disease Management, Disease Susceptibility, Humans, Immunomodulation drug effects, Immunotherapy methods, Neoplasms etiology, Neoplasms metabolism, Neoplasms pathology, Patient Outcome Assessment, T-Lymphocyte Subsets drug effects, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism, Tumor Microenvironment drug effects, Tumor Microenvironment genetics, Tumor Microenvironment immunology, Antineoplastic Agents, Immunological adverse effects, Immunotherapy adverse effects, Neoplasms therapy
- Abstract
Oncology has recently undergone a revolutionary change with widespread adoption of immunotherapy for many cancers. Immunotherapy using monoclonal antibodies against checkpoint molecules, including programmed death (PD)-1, PD ligand (PD-L)1, and cytotoxic T lymphocyte-associated antigen (CTLA)-4, is effective in a significant subset of patients. However, immune-related adverse events (irAEs) have emerged as frequent complications of checkpoint blockade, likely due to the physiological role of checkpoint pathways in regulating adaptive immunity and preventing autoimmunity. As immunotherapy becomes more common, a better understanding of the etiology of irAEs and ways to limit these events is needed. At the same time, studying these new therapy-related disorders provides an opportunity to better understand naturally occurring human autoimmune and inflammatory disorders, with the potential to improve therapies for cancer and autoimmune diseases., (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Published
- 2019
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20. Interferon-gamma drives programmed death-ligand 1 expression on islet β cells to limit T cell function during autoimmune diabetes.
- Author
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Osum KC, Burrack AL, Martinov T, Sahli NL, Mitchell JS, Tucker CG, Pauken KE, Papas K, Appakalai B, Spanier JA, and Fife BT
- Subjects
- Animals, Female, Humans, Interferon-gamma biosynthesis, Islets of Langerhans immunology, Mice, Mice, Inbred NOD, B7-H1 Antigen metabolism, Diabetes Mellitus, Type 1 immunology, Interferon-gamma metabolism, Islets of Langerhans metabolism, T-Lymphocytes immunology
- Abstract
Type 1 diabetes is caused by autoreactive T cell-mediated β cell destruction. Even though co-inhibitory receptor programmed death-1 (PD-1) restrains autoimmunity, the expression and regulation of its cognate ligands on β cell remains unknown. Here, we interrogated β cell-intrinsic programmed death ligand-1 (PD-L1) expression in mouse and human islets. We measured a significant increase in the level of PD-L1 surface expression and the frequency of PD-L1
+ β cells as non-obese diabetic (NOD) mice aged and developed diabetes. Increased β cell PD-L1 expression was dependent on T cell infiltration, as β cells from Rag1-deficient mice lacked PD-L1. Using Rag1-deficient NOD mouse islets, we determined that IFN-γ promotes β cell PD-L1 expression. We performed analogous experiments using human samples, and found a significant increase in β cell PD-L1 expression in type 1 diabetic samples compared to type 2 diabetic, autoantibody positive, and non-diabetic samples. Among type 1 diabetic samples, β cell PD-L1 expression correlated with insulitis. In vitro experiments with human islets from non-diabetic individuals showed that IFN-γ promoted β cell PD-L1 expression. These results suggest that insulin-producing β cells respond to pancreatic inflammation and IFN-γ production by upregulating PD-L1 expression to limit self-reactive T cells.- Published
- 2018
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21. The diverse functions of the PD1 inhibitory pathway.
- Author
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Sharpe AH and Pauken KE
- Subjects
- Antineoplastic Agents, Immunological therapeutic use, Autoimmunity immunology, B-Lymphocytes immunology, Humans, Killer Cells, Natural immunology, Signal Transduction immunology, Antibodies, Monoclonal therapeutic use, Immunotherapy methods, Lymphocyte Activation immunology, Neoplasms drug therapy, Programmed Cell Death 1 Receptor antagonists & inhibitors, Programmed Cell Death 1 Receptor metabolism, T-Lymphocytes immunology
- Abstract
T cell activation is a highly regulated process involving peptide-MHC engagement of the T cell receptor and positive costimulatory signals. Upon activation, coinhibitory 'checkpoints', including programmed cell death protein 1 (PD1), become induced to regulate T cells. PD1 has an essential role in balancing protective immunity and immunopathology, homeostasis and tolerance. However, during responses to chronic pathogens and tumours, PD1 expression can limit protective immunity. Recently developed PD1 pathway inhibitors have revolutionized cancer treatment for some patients, but the majority of patients do not show complete responses, and adverse events have been noted. This Review discusses the diverse roles of the PD1 pathway in regulating immune responses and how this knowledge can improve cancer immunotherapy as well as restore and/or maintain tolerance during autoimmunity and transplantation.
- Published
- 2018
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22. T-cell invigoration to tumour burden ratio associated with anti-PD-1 response.
- Author
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Huang AC, Postow MA, Orlowski RJ, Mick R, Bengsch B, Manne S, Xu W, Harmon S, Giles JR, Wenz B, Adamow M, Kuk D, Panageas KS, Carrera C, Wong P, Quagliarello F, Wubbenhorst B, D'Andrea K, Pauken KE, Herati RS, Staupe RP, Schenkel JM, McGettigan S, Kothari S, George SM, Vonderheide RH, Amaravadi RK, Karakousis GC, Schuchter LM, Xu X, Nathanson KL, Wolchok JD, Gangadhar TC, and Wherry EJ
- Subjects
- Antibodies, Monoclonal, Humanized administration & dosage, Antibodies, Monoclonal, Humanized immunology, Antibodies, Monoclonal, Humanized pharmacokinetics, Antibodies, Monoclonal, Humanized therapeutic use, CD8-Positive T-Lymphocytes cytology, CD8-Positive T-Lymphocytes metabolism, Female, Humans, Ki-67 Antigen immunology, Ki-67 Antigen metabolism, Male, Melanoma blood supply, Melanoma pathology, Neoplasm Staging, Phenotype, Treatment Outcome, CD8-Positive T-Lymphocytes immunology, Melanoma drug therapy, Melanoma immunology, Programmed Cell Death 1 Receptor antagonists & inhibitors, Programmed Cell Death 1 Receptor immunology, Tumor Burden immunology
- Abstract
Despite the success of monotherapies based on blockade of programmed cell death 1 (PD-1) in human melanoma, most patients do not experience durable clinical benefit. Pre-existing T-cell infiltration and/or the presence of PD-L1 in tumours may be used as indicators of clinical response; however, blood-based profiling to understand the mechanisms of PD-1 blockade has not been widely explored. Here we use immune profiling of peripheral blood from patients with stage IV melanoma before and after treatment with the PD-1-targeting antibody pembrolizumab and identify pharmacodynamic changes in circulating exhausted-phenotype CD8 T cells (T
ex cells). Most of the patients demonstrated an immunological response to pembrolizumab. Clinical failure in many patients was not solely due to an inability to induce immune reinvigoration, but rather resulted from an imbalance between T-cell reinvigoration and tumour burden. The magnitude of reinvigoration of circulating Tex cells determined in relation to pretreatment tumour burden correlated with clinical response. By focused profiling of a mechanistically relevant circulating T-cell subpopulation calibrated to pretreatment disease burden, we identify a clinically accessible potential on-treatment predictor of response to PD-1 blockade.- Published
- 2017
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23. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade.
- Author
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Pauken KE, Sammons MA, Odorizzi PM, Manne S, Godec J, Khan O, Drake AM, Chen Z, Sen DR, Kurachi M, Barnitz RA, Bartman C, Bengsch B, Huang AC, Schenkel JM, Vahedi G, Haining WN, Berger SL, and Wherry EJ
- Subjects
- Animals, B7-H1 Antigen antagonists & inhibitors, CD8-Positive T-Lymphocytes transplantation, Cell Lineage genetics, Cellular Reprogramming immunology, Female, Gene Regulatory Networks, Immunotherapy, Interleukin-7 metabolism, Mice, Mice, Inbred C57BL, Transcription, Genetic, B7-H1 Antigen genetics, CD8-Positive T-Lymphocytes immunology, Cellular Reprogramming genetics, Epigenesis, Genetic, Immunologic Memory genetics
- Abstract
Blocking Programmed Death-1 (PD-1) can reinvigorate exhausted CD8 T cells (T
EX ) and improve control of chronic infections and cancer. However, whether blocking PD-1 can reprogram TEX into durable memory T cells (TMEM ) is unclear. We found that reinvigoration of TEX in mice by PD-L1 blockade caused minimal memory development. After blockade, reinvigorated TEX became reexhausted if antigen concentration remained high and failed to become TMEM upon antigen clearance. TEX acquired an epigenetic profile distinct from that of effector T cells (TEFF ) and TMEM cells that was minimally remodeled after PD-L1 blockade. This finding suggests that TEX are a distinct lineage of CD8 T cells. Nevertheless, PD-1 pathway blockade resulted in transcriptional rewiring and reengagement of effector circuitry in the TEX epigenetic landscape. These data indicate that epigenetic fate inflexibility may limit current immunotherapies., (Copyright © 2016, American Association for the Advancement of Science.)- Published
- 2016
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24. Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade.
- Author
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Benci JL, Xu B, Qiu Y, Wu TJ, Dada H, Twyman-Saint Victor C, Cucolo L, Lee DSM, Pauken KE, Huang AC, Gangadhar TC, Amaravadi RK, Schuchter LM, Feldman MD, Ishwaran H, Vonderheide RH, Maity A, Wherry EJ, and Minn AJ
- Subjects
- Animals, B7-H1 Antigen metabolism, Cell Line, Tumor, Drug Resistance, Neoplasm, Heterografts, Humans, Interferons immunology, Melanoma drug therapy, Melanoma radiotherapy, Mice, Neoplasm Transplantation, STAT1 Transcription Factor, T-Lymphocytes immunology, CTLA-4 Antigen antagonists & inhibitors, Melanoma immunology, Melanoma therapy, Radioimmunotherapy
- Abstract
Therapeutic blocking of the PD1 pathway results in significant tumor responses, but resistance is common. We demonstrate that prolonged interferon signaling orchestrates PDL1-dependent and PDL1-independent resistance to immune checkpoint blockade (ICB) and to combinations such as radiation plus anti-CTLA4. Persistent type II interferon signaling allows tumors to acquire STAT1-related epigenomic changes and augments expression of interferon-stimulated genes and ligands for multiple T cell inhibitory receptors. Both type I and II interferons maintain this resistance program. Crippling the program genetically or pharmacologically interferes with multiple inhibitory pathways and expands distinct T cell populations with improved function despite expressing markers of severe exhaustion. Consequently, tumors resistant to multi-agent ICB are rendered responsive to ICB monotherapy. Finally, we observe that biomarkers for interferon-driven resistance associate with clinical progression after anti-PD1 therapy. Thus, the duration of tumor interferon signaling augments adaptive resistance and inhibition of the interferon response bypasses requirements for combinatorial ICB therapies., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
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25. Bioenergetic Insufficiencies Due to Metabolic Alterations Regulated by the Inhibitory Receptor PD-1 Are an Early Driver of CD8(+) T Cell Exhaustion.
- Author
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Bengsch B, Johnson AL, Kurachi M, Odorizzi PM, Pauken KE, Attanasio J, Stelekati E, McLane LM, Paley MA, Delgoffe GM, and Wherry EJ
- Subjects
- Animals, Antibodies, Neutralizing pharmacology, B7-H1 Antigen immunology, Cells, Cultured, Cellular Reprogramming, Cellular Senescence, Energy Metabolism, Glucose metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha genetics, Programmed Cell Death 1 Receptor genetics, Signal Transduction, TOR Serine-Threonine Kinases metabolism, CD8-Positive T-Lymphocytes immunology, Lymphocytic Choriomeningitis immunology, Lymphocytic choriomeningitis virus immunology, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha metabolism, Programmed Cell Death 1 Receptor metabolism
- Abstract
Dynamic reprogramming of metabolism is essential for T cell effector function and memory formation. However, the regulation of metabolism in exhausted CD8(+) T (Tex) cells is poorly understood. We found that during the first week of chronic lymphocytic choriomeningitis virus (LCMV) infection, before severe dysfunction develops, virus-specific CD8(+) T cells were already unable to match the bioenergetics of effector T cells generated during acute infection. Suppression of T cell bioenergetics involved restricted glucose uptake and use, despite persisting mechanistic target of rapamycin (mTOR) signaling and upregulation of many anabolic pathways. PD-1 regulated early glycolytic and mitochondrial alterations and repressed transcriptional coactivator PGC-1α. Improving bioenergetics by overexpression of PGC-1α enhanced function in developing Tex cells. Therapeutic reinvigoration by anti-PD-L1 reprogrammed metabolism in a subset of Tex cells. These data highlight a key metabolic control event early in exhaustion and suggest that manipulating glycolytic and mitochondrial metabolism might enhance checkpoint blockade outcomes., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
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26. Heterologous Vaccination and Checkpoint Blockade Synergize To Induce Antileukemia Immunity.
- Author
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Manlove LS, Schenkel JM, Manlove KR, Pauken KE, Williams RT, Vezys V, and Farrar MA
- Subjects
- Animals, Disease Models, Animal, Mice, Mice, Inbred C57BL, Mice, Knockout, Cell Cycle Checkpoints physiology, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma immunology, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma pathology, Vaccination
- Abstract
Checkpoint blockade-based immunotherapies are effective in cancers with high numbers of nonsynonymous mutations. In contrast, current paradigms suggest that such approaches will be ineffective in cancers with few nonsynonymous mutations. To examine this issue, we made use of a murine model of BCR-ABL(+) B-lineage acute lymphoblastic leukemia. Using a principal component analysis, we found that robust MHC class II expression, coupled with appropriate costimulation, correlated with lower leukemic burden. We next assessed whether checkpoint blockade or therapeutic vaccination could improve survival in mice with pre-established leukemia. Consistent with the low mutation load in our leukemia model, we found that checkpoint blockade alone had only modest effects on survival. In contrast, robust heterologous vaccination with a peptide derived from the BCR-ABL fusion (BAp), a key driver mutation, generated a small population of mice that survived long-term. Checkpoint blockade strongly synergized with heterologous vaccination to enhance overall survival in mice with leukemia. Enhanced survival did not correlate with numbers of BAp:I-A(b)-specific T cells, but rather with increased expression of IL-10, IL-17, and granzyme B and decreased expression of programmed death 1 on these cells. Our findings demonstrate that vaccination to key driver mutations cooperates with checkpoint blockade and allows for immune control of cancers with low nonsynonymous mutation loads., (Copyright © 2016 by The American Association of Immunologists, Inc.)
- Published
- 2016
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27. IL-15-Independent Maintenance of Tissue-Resident and Boosted Effector Memory CD8 T Cells.
- Author
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Schenkel JM, Fraser KA, Casey KA, Beura LK, Pauken KE, Vezys V, and Masopust D
- Subjects
- Animals, Cell Proliferation, Cells, Cultured, Cytotoxicity, Immunologic, Homeostasis, Immunization, Secondary, Mice, Mice, Inbred C57BL, Viral Vaccines immunology, CD8-Positive T-Lymphocytes immunology, Immunologic Memory, Interleukin-15 metabolism, Mucous Membrane immunology, T-Lymphocyte Subsets immunology
- Abstract
IL-15 regulates central and effector memory CD8 T cell (TCM and TEM, respectively) homeostatic proliferation, maintenance, and longevity. Consequently, IL-15 availability hypothetically defines the carrying capacity for total memory CD8 T cells within the host. In conflict with this hypothesis, previous observations demonstrated that boosting generates preternaturally abundant TEM that increases the total quantity of memory CD8 T cells in mice. In this article, we provide a potential mechanistic explanation by reporting that boosted circulating TEM do not require IL-15 for maintenance. We also investigated tissue-resident memory CD8 T cells (TRM), which protect nonlymphoid tissues from reinfection. We observed up to a 50-fold increase in the total magnitude of TRM in mouse mucosal tissues after boosting, suggesting that the memory T cell capacity in tissues is flexible and that TRM may not be under the same homeostatic regulation as primary central memory CD8 T cells and TEM Further analysis identified distinct TRM populations that depended on IL-15 for homeostatic proliferation and survival, depended on IL-15 for homeostatic proliferation but not for survival, or did not depend on IL-15 for either process. These observations on the numerical regulation of T cell memory indicate that there may be significant heterogeneity among distinct TRM populations and also argue against the common perception that developing vaccines that confer protection by establishing abundant TEM and TRM will necessarily erode immunity to previously encountered pathogens as the result of competition for IL-15., (Copyright © 2016 by The American Association of Immunologists, Inc.)
- Published
- 2016
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28. CD4(+) T cell anergy prevents autoimmunity and generates regulatory T cell precursors.
- Author
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Kalekar LA, Schmiel SE, Nandiwada SL, Lam WY, Barsness LO, Zhang N, Stritesky GL, Malhotra D, Pauken KE, Linehan JL, O'Sullivan MG, Fife BT, Hogquist KA, Jenkins MK, and Mueller DL
- Subjects
- Adoptive Transfer, Animals, Arthritis, Experimental immunology, CD4-Positive T-Lymphocytes immunology, Cell Proliferation, Cytokines immunology, Enzyme-Linked Immunosorbent Assay, Female, Flow Cytometry, Forkhead Transcription Factors immunology, Genes, T-Cell Receptor alpha, Immunoblotting, Male, Mice, Mice, Knockout, Neuropilin-1 metabolism, Pregnancy, Receptors, Antigen, T-Cell immunology, Reverse Transcriptase Polymerase Chain Reaction, Self Tolerance, Thymocytes immunology, Autoimmunity immunology, Cell Differentiation immunology, Clonal Anergy immunology, Histocompatibility, Maternal-Fetal immunology, Peripheral Tolerance immunology, Precursor Cells, T-Lymphoid immunology, T-Lymphocytes, Regulatory immunology
- Abstract
The role of anergy, an acquired state of T cell functional unresponsiveness, in natural peripheral tolerance remains unclear. In this study, we found that anergy was selectively induced in fetal antigen-specific maternal CD4(+) T cells during pregnancy. A naturally occurring subpopulation of anergic polyclonal CD4(+) T cells, enriched for self antigen-specific T cell antigen receptors, was also present in healthy hosts. Neuropilin-1 expression in anergic conventional CD4(+) T cells was associated with hypomethylation of genes related to thymic regulatory T cells (Treg cells), and this correlated with their ability to differentiate into Foxp3(+) Treg cells that suppressed immunopathology. Thus, our data suggest that not only is anergy induction important in preventing autoimmunity but also it generates the precursors for peripheral Treg cell differentiation.
- Published
- 2016
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29. PD-1 pathway-mediated regulation of islet-specific CD4 + T cell subsets in autoimmune diabetes.
- Author
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Martinov T, Spanier JA, Pauken KE, and Fife BT
- Abstract
Type 1 diabetes (T1D) is a CD4
+ T cell-driven autoimmune disease resulting from the destruction of insulin-producing pancreatic beta cells. Clinical evidence and studies in non-obese diabetic (NOD) mice suggest that insulin is a major autoantigen. With this in mind, we developed insulin B10-23 :IAg7 tetramer reagents to track insulin-specific CD4+ T cells in mice and interrogated the role of Programmed death-1 (PD-1) for peripheral tolerance. PD-1 is a T cell inhibitory receptor necessary to maintain tolerance and prevent T1D in NOD mice. PD-1 pathway inhibitors are increasingly used in the clinic for treating malignancies, and while many patients benefit, some develop adverse autoimmune events, including T1D. We therefore sought to understand the role of PD-1 in maintaining islet-specific tolerance in diabetes-resistant strains. B6.g7 mice express the same MHC Class II allele as NOD mice, have predominantly naïve insulin-specific CD4+ T cells in the periphery, and remain diabetes-free even after PD-1 pathway blockade. Here, we examined the trafficking potential of insulin-specific CD4+ T cells in NOD and B6.g7 mice with or without anti-PD-L1 treatment, and found that PD-L1 blockade preferentially increased the number of CD44high CXCR3+ insulin-specific cells in NOD but not B6.g7 mice. Additionally, we investigated whether pancreatic islets in NOD and B6.g7 mice expressed CXCL10, a lymphocyte homing chemokine and ligand for CXCR3. Anti-PD-L1 treated and control NOD mice had detectable CXCL10 expression in the islets, while B6.g7 islets did not. These data suggest that islet tolerance may be in part attributed to the pancreatic environment and in the absence of pancreas inflammation, chemotactic cytokines may be missing. This, together with our previous data showing that PD-1 pathway blockade preferentially affects effector but not anergic self-specific T cells has implications for the use of checkpoint blockade in treating tumor patients. Our work suggests that determining tumor- and self-specific CD4+ T cell activation status (naïve, effector or anergic) prior to initiation of immunotherapy would likely help to stratify individuals who would benefit from this therapy versus those who might have adverse effects or incomplete tumor control., Competing Interests: Conflicting Interests The authors have declared that no conflict of interests exist.- Published
- 2016
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30. SnapShot: T Cell Exhaustion.
- Author
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Pauken KE and Wherry EJ
- Subjects
- Animals, Humans, Programmed Cell Death 1 Receptor metabolism, Spleen immunology, T-Box Domain Proteins metabolism, T-Lymphocyte Subsets metabolism, T-Lymphocyte Subsets cytology, T-Lymphocyte Subsets immunology
- Published
- 2015
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31. CD39 Expression Identifies Terminally Exhausted CD8+ T Cells.
- Author
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Gupta PK, Godec J, Wolski D, Adland E, Yates K, Pauken KE, Cosgrove C, Ledderose C, Junger WG, Robson SC, Wherry EJ, Alter G, Goulder PJ, Klenerman P, Sharpe AH, Lauer GM, and Haining WN
- Subjects
- Animals, Arenaviridae Infections immunology, Chromatography, High Pressure Liquid, Chronic Disease, Disease Models, Animal, Flow Cytometry, HIV Infections immunology, Hepatitis C, Chronic immunology, Humans, Lymphocytic Choriomeningitis immunology, Lymphocytic choriomeningitis virus immunology, Mice, Mice, Inbred C57BL, Oligonucleotide Array Sequence Analysis, Antigens, CD immunology, Apyrase immunology, Biomarkers, CD8-Positive T-Lymphocytes immunology, RNA Virus Infections immunology, T-Lymphocyte Subsets immunology
- Abstract
Exhausted T cells express multiple co-inhibitory molecules that impair their function and limit immunity to chronic viral infection. Defining novel markers of exhaustion is important both for identifying and potentially reversing T cell exhaustion. Herein, we show that the ectonucleotidse CD39 is a marker of exhausted CD8+ T cells. CD8+ T cells specific for HCV or HIV express high levels of CD39, but those specific for EBV and CMV do not. CD39 expressed by CD8+ T cells in chronic infection is enzymatically active, co-expressed with PD-1, marks cells with a transcriptional signature of T cell exhaustion and correlates with viral load in HIV and HCV. In the mouse model of chronic Lymphocytic Choriomeningitis Virus infection, virus-specific CD8+ T cells contain a population of CD39high CD8+ T cells that is absent in functional memory cells elicited by acute infection. This CD39high CD8+ T cell population is enriched for cells with the phenotypic and functional profile of terminal exhaustion. These findings provide a new marker of T cell exhaustion, and implicate the purinergic pathway in the regulation of T cell exhaustion.
- Published
- 2015
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32. Adaptive Immunity to Leukemia Is Inhibited by Cross-Reactive Induced Regulatory T Cells.
- Author
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Manlove LS, Berquam-Vrieze KE, Pauken KE, Williams RT, Jenkins MK, and Farrar MA
- Subjects
- Animals, Cross Reactions, Fusion Proteins, bcr-abl genetics, Fusion Proteins, bcr-abl immunology, Mice, Mice, Knockout, Neoplasms, Experimental pathology, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, T-Lymphocytes, Regulatory pathology, Transforming Growth Factor beta1 genetics, Transforming Growth Factor beta1 immunology, Antigen Presentation, Neoplasms, Experimental immunology, Precursor Cell Lymphoblastic Leukemia-Lymphoma immunology, T-Lymphocytes, Regulatory immunology
- Abstract
BCR-ABL(+) acute lymphoblastic leukemia patients have transient responses to current therapies. However, the fusion of BCR to ABL generates a potential leukemia-specific Ag that could be a target for immunotherapy. We demonstrate that the immune system can limit BCR-ABL(+) leukemia progression although ultimately this immune response fails. To address how BCR-ABL(+) leukemia escapes immune surveillance, we developed a peptide: MHC class II tetramer that labels endogenous BCR-ABL-specific CD4(+) T cells. Naive mice harbored a small population of BCR-ABL-specific T cells that proliferated modestly upon immunization. The small number of naive BCR-ABL-specific T cells was due to negative selection in the thymus, which depleted BCR-ABL-specific T cells. Consistent with this observation, we saw that BCR-ABL-specific T cells were cross-reactive with an endogenous peptide derived from ABL. Despite this cross-reactivity, the remaining population of BCR-ABL reactive T cells proliferated upon immunization with the BCR-ABL fusion peptide and adjuvant. In response to BCR-ABL(+) leukemia, BCR-ABL-specific T cells proliferated and converted into regulatory T (Treg) cells, a process that was dependent on cross-reactivity with self-antigen, TGF-β1, and MHC class II Ag presentation by leukemic cells. Treg cells were critical for leukemia progression in C57BL/6 mice, as transient Treg cell ablation led to extended survival of leukemic mice. Thus, BCR-ABL(+) leukemia actively suppresses antileukemia immune responses by converting cross-reactive leukemia-specific T cells into Treg cells., (Copyright © 2015 by The American Association of Immunologists, Inc.)
- Published
- 2015
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33. Genetic absence of PD-1 promotes accumulation of terminally differentiated exhausted CD8+ T cells.
- Author
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Odorizzi PM, Pauken KE, Paley MA, Sharpe A, and Wherry EJ
- Subjects
- Adoptive Transfer, Animals, Bromodeoxyuridine, Cell Differentiation genetics, Cell Proliferation physiology, Flow Cytometry, Mice, Programmed Cell Death 1 Receptor deficiency, CD8-Positive T-Lymphocytes immunology, Cell Differentiation immunology, Lymphocytic Choriomeningitis immunology, Programmed Cell Death 1 Receptor metabolism
- Abstract
Programmed Death-1 (PD-1) has received considerable attention as a key regulator of CD8(+) T cell exhaustion during chronic infection and cancer because blockade of this pathway partially reverses T cell dysfunction. Although the PD-1 pathway is critical in regulating established "exhausted" CD8(+) T cells (TEX cells), it is unclear whether PD-1 directly causes T cell exhaustion. We show that PD-1 is not required for the induction of exhaustion in mice with chronic lymphocytic choriomeningitis virus (LCMV) infection. In fact, some aspects of exhaustion are more severe with genetic deletion of PD-1 from the onset of infection. Increased proliferation between days 8 and 14 postinfection is associated with subsequent decreased CD8(+) T cell survival and disruption of a critical proliferative hierarchy necessary to maintain exhausted populations long term. Ultimately, the absence of PD-1 leads to the accumulation of more cytotoxic, but terminally differentiated, CD8(+) TEX cells. These results demonstrate that CD8(+) T cell exhaustion can occur in the absence of PD-1. They also highlight a novel role for PD-1 in preserving TEX cell populations from overstimulation, excessive proliferation, and terminal differentiation., (© 2015 Odorizzi et al.)
- Published
- 2015
- Full Text
- View/download PDF
34. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer.
- Author
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Twyman-Saint Victor C, Rech AJ, Maity A, Rengan R, Pauken KE, Stelekati E, Benci JL, Xu B, Dada H, Odorizzi PM, Herati RS, Mansfield KD, Patsch D, Amaravadi RK, Schuchter LM, Ishwaran H, Mick R, Pryma DA, Xu X, Feldman MD, Gangadhar TC, Hahn SM, Wherry EJ, Vonderheide RH, and Minn AJ
- Subjects
- Animals, B7-H1 Antigen metabolism, Female, Humans, Melanoma pathology, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Receptors, Antigen, T-Cell drug effects, Receptors, Antigen, T-Cell immunology, Receptors, Antigen, T-Cell metabolism, T-Lymphocytes cytology, T-Lymphocytes immunology, T-Lymphocytes, Regulatory drug effects, T-Lymphocytes, Regulatory immunology, T-Lymphocytes, Regulatory radiation effects, B7-H1 Antigen antagonists & inhibitors, CTLA-4 Antigen antagonists & inhibitors, Cell Cycle Checkpoints drug effects, Melanoma drug therapy, Melanoma immunology, Melanoma radiotherapy, T-Lymphocytes drug effects, T-Lymphocytes radiation effects
- Abstract
Immune checkpoint inhibitors result in impressive clinical responses, but optimal results will require combination with each other and other therapies. This raises fundamental questions about mechanisms of non-redundancy and resistance. Here we report major tumour regressions in a subset of patients with metastatic melanoma treated with an anti-CTLA4 antibody (anti-CTLA4) and radiation, and reproduced this effect in mouse models. Although combined treatment improved responses in irradiated and unirradiated tumours, resistance was common. Unbiased analyses of mice revealed that resistance was due to upregulation of PD-L1 on melanoma cells and associated with T-cell exhaustion. Accordingly, optimal response in melanoma and other cancer types requires radiation, anti-CTLA4 and anti-PD-L1/PD-1. Anti-CTLA4 predominantly inhibits T-regulatory cells (Treg cells), thereby increasing the CD8 T-cell to Treg (CD8/Treg) ratio. Radiation enhances the diversity of the T-cell receptor (TCR) repertoire of intratumoral T cells. Together, anti-CTLA4 promotes expansion of T cells, while radiation shapes the TCR repertoire of the expanded peripheral clones. Addition of PD-L1 blockade reverses T-cell exhaustion to mitigate depression in the CD8/Treg ratio and further encourages oligoclonal T-cell expansion. Similarly to results from mice, patients on our clinical trial with melanoma showing high PD-L1 did not respond to radiation plus anti-CTLA4, demonstrated persistent T-cell exhaustion, and rapidly progressed. Thus, PD-L1 on melanoma cells allows tumours to escape anti-CTLA4-based therapy, and the combination of radiation, anti-CTLA4 and anti-PD-L1 promotes response and immunity through distinct mechanisms.
- Published
- 2015
- Full Text
- View/download PDF
35. Cutting edge: identification of autoreactive CD4+ and CD8+ T cell subsets resistant to PD-1 pathway blockade.
- Author
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Pauken KE, Nelson CE, Martinov T, Spanier JA, Heffernan JR, Sahli NL, Quarnstrom CF, Osum KC, Schenkel JM, Jenkins MK, Blazar BR, Vezys V, and Fife BT
- Subjects
- Animals, Autoimmune Diseases genetics, Autoimmune Diseases pathology, B7-H1 Antigen genetics, B7-H1 Antigen immunology, CD4-Positive T-Lymphocytes pathology, CD8-Positive T-Lymphocytes pathology, Cell Differentiation genetics, Cell Differentiation immunology, Disease Models, Animal, Disease Susceptibility immunology, Disease Susceptibility pathology, Female, Immune Tolerance genetics, Mice, Mice, Inbred NOD, Mice, Knockout, Programmed Cell Death 1 Receptor genetics, Signal Transduction genetics, Autoimmune Diseases immunology, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Clonal Anergy, Programmed Cell Death 1 Receptor immunology, Signal Transduction immunology
- Abstract
Programmed death-1 (PD-1) promotes T cell tolerance. Despite therapeutically targeting this pathway for chronic infections and tumors, little is known about how different T cell subsets are affected during blockade. We examined PD-1/PD ligand 1 (PD-L1) regulation of self-antigen-specific CD4 and CD8 T cells in autoimmune-susceptible models. PD-L1 blockade increased insulin-specific effector CD4 T cells in type 1 diabetes. However, anergic islet-specific CD4 T cells were resistant to PD-L1 blockade. Additionally, PD-L1 was critical for induction, but not maintenance, of CD8 T cell intestinal tolerance. PD-L1 blockade enhanced functionality of effector T cells, whereas established tolerant or anergic T cells were not dependent on PD-1/PD-L1 signaling to remain unresponsive. This highlights the existence of Ag-experienced T cell subsets that do not rely on PD-1/PD-L1 regulation. These findings illustrate how positive treatment outcomes and autoimmunity development during PD-1/PD-L1 inhibition are linked to the differentiation state of a T cell., (Copyright © 2015 by The American Association of Immunologists, Inc.)
- Published
- 2015
- Full Text
- View/download PDF
36. Overcoming T cell exhaustion in infection and cancer.
- Author
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Pauken KE and Wherry EJ
- Subjects
- Animals, B7-H1 Antigen antagonists & inhibitors, Chronic Disease, Hepatitis therapy, Humans, Neoplasms therapy, Programmed Cell Death 1 Receptor antagonists & inhibitors, B7-H1 Antigen immunology, Hepatitis immunology, Hepatitis pathology, Neoplasms immunology, Neoplasms pathology, Programmed Cell Death 1 Receptor immunology, T-Lymphocytes immunology
- Abstract
Inhibitors of the Programmed Cell Death 1: Programmed Cell Death 1 ligand 1 (PD-1:PD-L1) pathway, a central regulator of T cell exhaustion, have been recently shown to be effective for treatment of different cancers. However, clinical responses are mixed, highlighting the need to better understand the mechanisms of action of PD-1:PD-L1, the role of this pathway in immunity to different tumors, and the molecular and cellular effects of PD-1 blockade. Here, we review the molecular regulation of T cell exhaustion, placing recent findings on PD-1 blockade therapies in cancer in the context of the broader understanding of the roles of the PD-1:PD-L1 pathway in T cell exhaustion during chronic infection. We discuss the current understanding of the mechanisms involved in reversing T cell exhaustion, and outline critical areas of focus for future research, both basic and clinical., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
37. TIGIT and CD226: tipping the balance between costimulatory and coinhibitory molecules to augment the cancer immunotherapy toolkit.
- Author
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Pauken KE and Wherry EJ
- Subjects
- Animals, Humans, Antigens, Differentiation, T-Lymphocyte metabolism, CD8-Positive T-Lymphocytes immunology, Lymphocytic Choriomeningitis immunology, Neoplasms immunology, Receptors, Immunologic metabolism
- Abstract
Combination therapies are becoming a focal point in cancer immunotherapy. In this issue of Cancer Cell, Johnston and colleagues identify the TIGIT/CD226 pathway, which provides significant interest for combination with PD-1 pathway blockade to improve anticancer CD8(+) T cell responses, because it acts by a novel mechanism to regulate CD8(+) T cell functions within the tumor microenvironment., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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- View/download PDF
38. T cell memory. Resident memory CD8 T cells trigger protective innate and adaptive immune responses.
- Author
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Schenkel JM, Fraser KA, Beura LK, Pauken KE, Vezys V, and Masopust D
- Subjects
- Animals, Antigens, Viral immunology, Female, Immunity, Humoral immunology, Interferon-gamma immunology, Mice, Mice, Inbred C57BL, Mucous Membrane immunology, Mucous Membrane virology, Vascular Cell Adhesion Molecule-1 immunology, Adaptive Immunity immunology, CD8-Positive T-Lymphocytes immunology, Immunity, Innate immunology, Immunologic Memory, Virus Diseases immunology
- Abstract
The pathogen recognition theory dictates that, upon viral infection, the innate immune system first detects microbial products and then responds by providing instructions to adaptive CD8 T cells. Here, we show in mice that tissue resident memory CD8 T cells (T(RM) cells), non-recirculating cells located at common sites of infection, can achieve near-sterilizing immunity against viral infections by reversing this flow of information. Upon antigen resensitization within the mouse female reproductive mucosae, CD8(+) T(RM) cells secrete cytokines that trigger rapid adaptive and innate immune responses, including local humoral responses, maturation of local dendritic cells, and activation of natural killer cells. This provided near-sterilizing immunity against an antigenically unrelated viral infection. Thus, CD8(+) T(RM) cells rapidly trigger an antiviral state by amplifying receptor-derived signals from previously encountered pathogens., (Copyright © 2014, American Association for the Advancement of Science.)
- Published
- 2014
- Full Text
- View/download PDF
39. Cutting edge: type 1 diabetes occurs despite robust anergy among endogenous insulin-specific CD4 T cells in NOD mice.
- Author
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Pauken KE, Linehan JL, Spanier JA, Sahli NL, Kalekar LA, Binstadt BA, Moon JJ, Mueller DL, Jenkins MK, and Fife BT
- Subjects
- Animals, Insulin immunology, Interferon-gamma metabolism, Mice, Mice, Inbred NOD, Pancreas cytology, Pancreas immunology, CD4-Positive T-Lymphocytes immunology, Clonal Anergy immunology, Diabetes Mellitus, Experimental immunology, Diabetes Mellitus, Type 1 immunology
- Abstract
Insulin-specific CD4(+) T cells are required for type 1 diabetes. How these cells are regulated and how tolerance breaks down are poorly understood because of a lack of reagents. Therefore, we used an enrichment method and tetramer reagents to track insulin-specific CD4(+) T cells in diabetes-susceptible NOD and resistant B6 mice expressing I-A(g7). Insulin-specific cells were detected in both strains, but they only became activated, produced IFN-γ, and infiltrated the pancreas in NOD mice. Unexpectedly, the majority of Ag-experienced cells in NOD mice displayed an anergic phenotype, but this population decreased with age as tolerance was lost. B6 mice expressing I-A(g7) were protected because insulin-specific cells did not become effector or anergic T cells but remained naive. These data suggest that NOD mice promote tolerance through anergy induction, but a small proportion of autoreactive T cells escape anergy to provoke type 1 diabetes.
- Published
- 2013
- Full Text
- View/download PDF
40. PD-1, but not PD-L1, expressed by islet-reactive CD4+ T cells suppresses infiltration of the pancreas during type 1 diabetes.
- Author
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Pauken KE, Jenkins MK, Azuma M, and Fife BT
- Subjects
- Adoptive Transfer, Animals, B7-H1 Antigen genetics, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes pathology, Cell Differentiation physiology, Cell Proliferation, Diabetes Mellitus, Type 1 immunology, Diabetes Mellitus, Type 1 pathology, Islets of Langerhans immunology, Islets of Langerhans metabolism, Islets of Langerhans pathology, Lymphocyte Activation physiology, Mice, Mice, Inbred NOD, Pancreas immunology, Pancreas pathology, Programmed Cell Death 1 Receptor genetics, B7-H1 Antigen metabolism, CD4-Positive T-Lymphocytes metabolism, Diabetes Mellitus, Type 1 metabolism, Pancreas metabolism, Programmed Cell Death 1 Receptor metabolism
- Abstract
The inhibitory receptor programmed death-1 (PD-1) constrains type 1 diabetes (T1D) in the nonobese diabetic (NOD) mouse. However, how PD-1 influences diabetogenic CD4(+) T cells during natural diabetes is not fully understood. To address this question, we developed a novel model to investigate antigen-specific CD4(+) T cells under physiological conditions in vivo. We transferred a low number of naïve CD4(+) T cells from the BDC2.5 mouse into prediabetic NOD mice to mimic a physiological precursor frequency and allowed the cells to become primed by endogenous autoantigen. Transferred BDC2.5 T cells became activated, differentiated into T-bet(+) IFN-γ-producing cells, and infiltrated the pancreas. In this model, loss of PD-1, but not programmed death ligand-1 (PD-L1), on the antigen-specific CD4(+) T cell resulted in increased cell numbers in the spleen, pancreas-draining lymph node, and pancreas. PD-1 deficiency also increased expression of the chemokine receptor CXCR3. Lastly, histological data showed that a loss of PD-1 caused BDC2.5 cells to penetrate deep into the islet core, resulting in conversion from peri-insulitis to destructive insulitis. These data support a model by which PD-1 regulates islet-reactive CD4(+) T cells in a cell intrinsic manner by suppressing proliferation, inhibiting infiltration of the pancreas, and limiting diabetes.
- Published
- 2013
- Full Text
- View/download PDF
41. The role of the PD-1 pathway in autoimmunity and peripheral tolerance.
- Author
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Fife BT and Pauken KE
- Subjects
- Animals, Humans, Lymphocyte Activation immunology, Programmed Cell Death 1 Receptor, Receptors, Antigen, T-Cell physiology, Signal Transduction immunology, T-Lymphocytes immunology, T-Lymphocytes metabolism, Antigens, CD physiology, Apoptosis Regulatory Proteins physiology, Autoantibodies biosynthesis, Immune Tolerance immunology
- Abstract
Programmed death-1 (PD-1) is a surface receptor critical for the regulation of T cell function during immunity and tolerance. PD-1 interactions with its ligands PD-L1 and PD-L2 inhibit T cell effector functions in an antigen-specific manner. This paper examines the role of PD-1 in limiting autoreactivity and establishing self-tolerance and discusses the hypothesis that PD-1 ligand (PD-L) expression both spatially and temporally dictates the fate of self-reactive T cells during the breakdown of peripheral tolerance and development of autoimmunity. We focus our discussion on the role of PD-1/PD-L interactions during peripheral tolerance, the differential role for PD-L1 and PD-L2 in response to environmental or self-antigens, and the impact of PD-1 signaling on dynamic T cell motility and the T cell receptor (TCR) stop signal. Finally, we discuss the potential to selectively target the PD-1 pathway therapeutically to alter T cell function during autoimmunity., (© 2011 New York Academy of Sciences.)
- Published
- 2011
- Full Text
- View/download PDF
42. Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal.
- Author
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Fife BT, Pauken KE, Eagar TN, Obu T, Wu J, Tang Q, Azuma M, Krummel MF, and Bluestone JA
- Subjects
- Animals, Antigens, CD immunology, Antigens, CD metabolism, Antigens, Surface metabolism, Apoptosis Regulatory Proteins metabolism, B7-1 Antigen metabolism, B7-H1 Antigen, CTLA-4 Antigen, Cell Movement, Dendritic Cells immunology, Diabetes Mellitus, Experimental immunology, Diabetes Mellitus, Experimental metabolism, Diabetes Mellitus, Type 1 immunology, Diabetes Mellitus, Type 1 metabolism, Islets of Langerhans immunology, Islets of Langerhans metabolism, Islets of Langerhans Transplantation, Lymphocyte Activation, Membrane Glycoproteins metabolism, Mice, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, Transgenic, Peptides metabolism, Programmed Cell Death 1 Receptor, Antigens, Surface immunology, Apoptosis Regulatory Proteins immunology, B7-1 Antigen immunology, Immune Tolerance, Membrane Glycoproteins immunology, Peptides immunology, Receptors, Antigen, T-Cell immunology, Signal Transduction immunology
- Abstract
Programmed death 1 (PD-1) is an inhibitory molecule expressed on activated T cells; however, the biological context in which PD-1 controls T cell tolerance remains unclear. Using two-photon laser-scanning microscopy, we show here that unlike naive or activated islet antigen-specific T cells, tolerized islet antigen-specific T cells moved freely and did not swarm around antigen-bearing dendritic cells (DCs) in pancreatic lymph nodes. Inhibition of T cell antigen receptor (TCR)-driven stop signals depended on continued interactions between PD-1 and its ligand, PD-L1, as antibody blockade of PD-1 or PD-L1 resulted in lower T cell motility, enhanced T cell-DC contacts and caused autoimmune diabetes. Blockade of the immunomodulatory receptor CTLA-4 did not alter T cell motility or abrogate tolerance. Thus, PD-1-PD-L1 interactions maintain peripheral tolerance by mechanisms fundamentally distinct from those of CTLA-4.
- Published
- 2009
- Full Text
- View/download PDF
43. Lutzomyia longipalpis salivary peptide maxadilan alters murine dendritic cell expression of CD80/86, CCR7, and cytokine secretion and reprograms dendritic cell-mediated cytokine release from cultures containing allogeneic T cells.
- Author
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Wheat WH, Pauken KE, Morris RV, and Titus RG
- Subjects
- Animals, B7-1 Antigen biosynthesis, B7-2 Antigen biosynthesis, CD4-Positive T-Lymphocytes cytology, CD4-Positive T-Lymphocytes metabolism, Cell Proliferation, Cells, Cultured, Cytokines antagonists & inhibitors, Dendritic Cells metabolism, Down-Regulation immunology, Female, Gene Expression Regulation immunology, Isoantigens immunology, Mice, Mice, Inbred BALB C, Mice, Inbred C3H, Mice, Inbred C57BL, Receptors, CCR7 antagonists & inhibitors, Up-Regulation immunology, B7-1 Antigen genetics, B7-2 Antigen genetics, CD4-Positive T-Lymphocytes immunology, Cytokines metabolism, Dendritic Cells immunology, Insect Proteins physiology, Psychodidae immunology, Receptors, CCR7 biosynthesis, Salivary Proteins and Peptides physiology
- Abstract
Leishmania protozoan parasites, the etiologic agent of leishmaniasis, are transmitted exclusively by phlebotomine sand flies of the genera Phlebotomus and Lutzomyia. In addition to parasites, the infectious bite inoculum contains arthropod salivary components. One well-characterized salivary component from Lutzomyia longipalpis is maxadilan (MAX), a vasodilator acting via the type I receptor for the pituitary cyclic AMP activating peptide. MAX has been shown to elicit immunomodulatory effects potentially dictating immune responses to Leishmania parasites. When exposed to MAX, both resting and LPS-stimulated dendritic cells (DCs) show reduced CD80 and CD86 expression on most DCs in vitro. However, CD86 expression is increased significantly on a subpopulation of DCs. Furthermore, MAX treatment promoted secretion of type 2 cytokines (IL-6 and IL-10) while reducing production of type 1 cytokines (IL-12p40, TNF-alpha, and IFN-gamma) by LPS-stimulated DCs. A similar trend was observed in cultures of MAX-treated DCs containing naive allogeneic CD4(+) T cells: type 2 cytokines (IL-6 and IL-13) increased while type 1 cytokines (TNF-alpha and IFN-gamma) decreased. Additionally, the proinflammatory cytokine IL-1beta was increased in cultures containing MAX-treated mature DCs. MAX treatment of LPS-stimulated DCs also prevented optimal surface expression of CCR7 in vitro. These MAX-dependent effects were evident in DCs from both Leishmania major-susceptible (BALB/c) and -resistant (C3H/HeN) murine strains. These data suggest that modification of DC phenotype and function by MAX likely affects crucial cellular components that determine the pathological response to infection with Leishmania.
- Published
- 2008
- Full Text
- View/download PDF
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