7 results on '"Diana Graves"'
Search Results
2. Efferocytosis drives myeloid NLRP3 dependent inflammasome signaling secretion of IL-1β to promote tumor growth
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Cara Lang, Sohini Roy, Yu Wang, Diana Graves, Yaomin Xu, C. Henrique Serezani, Michael Korrer, and Young J. Kim
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inflammasome ,efferocytosis ,NLRP3 ,IL-1β ,immunotherapy ,tumor associated macrophage ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Caspase-1 signaling in myeloid suppressor cells can promote T-cell independent cancer progression, but the regulation of inflammasome signaling within the highly heterogeneous myeloid population in the tumor milieu remains elusive. To resolve this complexity, single cell transcriptomic profile of Head and Neck Squamous Cell Carcinoma (HNSCC) identified distinct inflammasome-associated genes within specific clusters of tumor-infiltrating myeloid cells. Among these myeloid cells, the sensor protein, NLRP3, and downstream effector IL-1β transcripts were enriched in discreet monocytic and macrophage subtypes in the TME. We showed that deletion of NLRP3, but not AIM2, phenocopied caspase-1/IL-1β dependent tumor progression in vivo. Paradoxically, we found myeloid-intrinsic caspase-1 signaling increased myeloid survival contrary to what would be predicted from the canonical pyroptotic function of caspase-1. This myeloid NLRP3/IL-1β signaling axis promotion of tumor growth was found to be gasdermin D independent. Mechanistically, we found that phagocyte-mediated efferocytosis of dying tumor cells in the TME directly activated NLRP3-dependent inflammasome signaling to drive IL-1β secretion. Subsequently we showed that NLRP3-mediated IL-1β production drives tumor growth in vivo. Dynamic RNA velocity analysis showed a robust directional flow from efferocytosis gene-set high macrophages to an inflammasome gene-set high macrophage population. We provide a novel efferocytosis-dependent inflammasome signaling pathway which mediates homeostatic tumor cell apoptosis that characterizes chronic inflammation-induced malignancy.
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- 2022
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3. MuSyC dosing of adjuvanted cancer vaccines optimizes antitumor responses
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David Taylor, Christian T. Meyer, Diana Graves, Rupashree Sen, Juan Fu, Emily Tran, Bilal Mirza, Gabriel Rodriguez, Cara Lang, Hanwen Feng, Vito Quaranta, John T. Wilson, Young J. Kim, and Michael J. Korrer
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Multidimensional Synergy of Combinations (MuSyC) ,TLR7/8 agonist ,STING agonists ,cancer vaccine ,antitumor/cytotoxic activity ,T-cell priming ,Immunologic diseases. Allergy ,RC581-607 - Abstract
With the clinical approval of T-cell–dependent immune checkpoint inhibitors for many cancers, therapeutic cancer vaccines have re-emerged as a promising immunotherapy. Cancer vaccines require the addition of immunostimulatory adjuvants to increase vaccine immunogenicity, and increasingly multiple adjuvants are used in combination to bolster further and shape cellular immunity to tumor antigens. However, rigorous quantification of adjuvants’ synergistic interactions is challenging due to partial redundancy in costimulatory molecules and cytokine production, leading to the common assumption that combining both adjuvants at the maximum tolerated dose results in optimal efficacy. Herein, we examine this maximum dose assumption and find combinations of these doses are suboptimal. Instead, we optimized dendritic cell activation by extending the Multidimensional Synergy of Combinations (MuSyC) framework that measures the synergy of efficacy and potency between two vaccine adjuvants. Initially, we performed a preliminary in vitro screening of clinically translatable adjuvant receptor targets (TLR, STING, NLL, and RIG-I). We determined that STING agonist (CDN) plus TLR4 agonist (MPL-A) or TLR7/8 agonist (R848) as the best pairwise combinations for dendritic cell activation. In addition, we found that the combination of R848 and CDN is synergistically efficacious and potent in activating both murine and human antigen-presenting cells (APCs) in vitro. These two selected adjuvants were then used to estimate a MuSyC-dose optimized for in vivo T-cell priming using ovalbumin-based peptide vaccines. Finally, using B16 melanoma and MOC1 head and neck cancer models, MuSyC-dose–based adjuvating of cancer vaccines improved the antitumor response, increased tumor-infiltrating lymphocytes, and induced novel myeloid tumor infiltration changes. Further, the MuSyC-dose–based adjuvants approach did not cause additional weight changes or increased plasma cytokine levels compared to CDN alone. Collectively, our findings offer a proof of principle that our MuSyC-extended approach can be used to optimize cancer vaccine formulations for immunotherapy.
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- 2022
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4. 903 Human cancer-associated fibroblast subsets can predict immune checkpoint response in head and neck cancer patients
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Yu Wang, Andrea Califano, Young Kim, Michael Gibson, Charles Drake, Yaomin Xu, Ravindra Uppaluri, Adam Luginbuhl, Aleksandar Obradovic, Joseph Curry, Michael Korrer, Diana Graves, Sohini Roy, and Paula Hurley
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2021
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5. Supplementary Table S1 from Immunostimulatory Cancer-Associated Fibroblast Subpopulations Can Predict Immunotherapy Response in Head and Neck Cancer
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Young J. Kim, Andrea Califano, Charles G. Drake, Ravindra Uppaluri, X. Shirley Liu, Peng Jiang, Paula Hurley, Kamran Idrees, Michael Gibson, Joseph Curry, Adam Luginbuhl, Yaomin Xu, Abdullah Naveed, Sohini Roy, Yu Wang, Michael Korrer, Diana Graves, and Aleksandar Obradovic
- Abstract
Supplementary Table S1 from Immunostimulatory Cancer-Associated Fibroblast Subpopulations Can Predict Immunotherapy Response in Head and Neck Cancer
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- 2023
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6. Supplementary Figure S8 from Immunostimulatory Cancer-Associated Fibroblast Subpopulations Can Predict Immunotherapy Response in Head and Neck Cancer
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Young J. Kim, Andrea Califano, Charles G. Drake, Ravindra Uppaluri, X. Shirley Liu, Peng Jiang, Paula Hurley, Kamran Idrees, Michael Gibson, Joseph Curry, Adam Luginbuhl, Yaomin Xu, Abdullah Naveed, Sohini Roy, Yu Wang, Michael Korrer, Diana Graves, and Aleksandar Obradovic
- Abstract
Supplementary Figure S8 from Immunostimulatory Cancer-Associated Fibroblast Subpopulations Can Predict Immunotherapy Response in Head and Neck Cancer
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- 2023
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7. 903 Human cancer-associated fibroblast subsets can predict immune checkpoint response in head and neck cancer patients
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Andrea Califano, Paula Hurley, Adam Luginbuhl, Michael J. Korrer, Yu Wang, Joseph Curry, Charles G. Drake, Yaomin Xu, Aleksandar Obradovic, Sohini Roy, Diana Graves, Young J. Kim, Ravindra Uppaluri, and Michael K. Gibson
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Pharmacology ,Cancer Research ,business.industry ,Tumor-infiltrating lymphocytes ,medicine.medical_treatment ,Immunology ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Cancer ,Immunotherapy ,Pembrolizumab ,medicine.disease ,Head and neck squamous-cell carcinoma ,Oncology ,Cancer immunotherapy ,Pancreatic cancer ,medicine ,Cancer research ,Molecular Medicine ,Immunology and Allergy ,Nivolumab ,business ,RC254-282 - Abstract
BackgroundUse of anti-PD-1 immune checkpoint inhibitors (ICI) is currently the first line therapy for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), but critical work remains in identifying factors guiding resistance mechanisms.1 2 While recent studies have specifically implicated cancer-associated fibroblasts (CAFs) as potential mediators of immunotherapy response, the immunoregulatory role of CAFs in head and neck cancer has not been thoroughly explored.3–5MethodsTo determine if there are changes in cell populations associated with anti-PD-1 therapy in head and neck cancer patients, we performed high dimensional single-cell RNA sequencing (scRNA-SEQ) from a neoadjuvant trial of 50 advanced-stage head and neck squamous cell carcinoma (HNSCC) patients that were treated with the anti-PD-1 therapy, nivolumab, for the duration of one month. Tumor specimens were analyzed pre- and post-treatment with single-cell RNA sequencing performed on 4 patients as well as bulk RNA sequencing on 40 patients. Matched scRNA-SEQ data was analyzed using the Algorithm for the Reconstruction of Accurate Cellular Networks (ARACNe) and Virtual Inference of Protein-activity by Enriched Regulon (VIPER) bioinformatic analysis platform to determine TME cells that correlated with response and resistance to nivolumab.6 For CAF functional studies, surgical tumor specimens were processed and enriched for CAF subtypes, and these were co-cultured with T cells from peripheral blood and tumor infiltrating lymphocytes.ResultsWe identified 14 distinct cell types present in HNSCC patients. Of these 14 cell types, the fibroblast subtype showed significant changes in abundance following nivolumab treatment. We identified 5 distinct clusters of cancer-associated fibroblast subsets (HNCAF-0, 1, 2, 3, and 4) of which, two clusters, HNCAF-0 and HNCAF-3 were predictive of patient response to anti-PD-1 therapy. To determine the significance of these CAF subsets’ function, we isolated HNCAF-0/3 cells from primary HNSCC tumor specimens and co-cultured with primary human T cells. Analysis by flow cytometry showed that HNCAF-0/3 reduced TGFβ-dependent PD-1+TIM-3+ exhaustion of T cells and increased CD103+NKG2A+ resident memory phenotype and cytotoxicity to enhance overall function.ConclusionsTo our knowledge, we are the first to characterize CAF heterogeneity within the head and neck TME and show direct immunostimulatory activity of CAFs. Our findings demonstrate the functional importance of CAF subsets in modulating the immunoregulatory milieu of the human HNSCC, and we have identified clinically actionable CAF subtypes that can be used as a biomarker of response and resistance in future clinical trials.Trial RegistrationNCT03238365ReferencesFerris RL, Blumenschein Jr G, Fayette J, Guigay J, Colevas AD, Licitra L, Harrington K, Kasper S, Vokes EE, Even C, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 2016;375:1856–1867.Seiwert TY, Burtness B, Mehra R, Weiss J, Berger R, Eder JP, Heath K, McClanahan T, Lunceford J, Gause C, et al. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol 2016;17:956–965.Dominguez CX, Muller S, Keerthivasan S, Koeppen H, Hung J, Gierke S, Breart B, Foreman O, Bainbridge TW, Castiglioni A, et al. Single-cell RNA sequencing reveals stromal evolution into LRRC15(+) myofibroblasts as a determinant of patient response to cancer immunotherapy. Cancer Discov 2020;10:232–253.Feig C, Jones JO, Kraman M, Wells RJ, Deonarine A, Chan DS, Connell CM, Roberts EW, Zhao Q, Caballero OL, et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci U S A 2013;110:20212–20217.Kieffer Y, Hocine HR, Gentric G, Pelon F, Bernard C, Bourachot B, Lameiras S, Albergante L, Bonneau C, Guyard A, et al. Single-cell analysis reveals fibroblast clusters linked to immunotherapy resistance in cancer. Cancer Discov 2020;10:1330–1351.Obradovic A, Chowdhury N, Haake SM, Ager C, Wang V, Vlahos L, Guo XV, Aggen DH, Rathmell WK, Jonasch E, et al. Single-cell protein activity analysis identifies recurrence-associated renal tumor macrophages. Cell 2021;184:2988–3005.Ethics ApprovalPatients provided informed consent for this work. All experimental procedures were approved by the Institutional Review Board of Vanderbilt University Medical Center (IRB: 171883).
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- 2021
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