Search

Your search keyword '"Schenkel, Jason M."' showing total 215 results
Start Over Author "Schenkel, Jason M."
215 results on '"Schenkel, Jason M."'

2. Single-cell analyses identify circulating anti-tumor CD8 T cells and markers for their enrichment

Author

Pauken, Kristen E, Shahid, Osmaan, Lagattuta, Kaitlyn A, Mahuron, Kelly M, Luber, Jacob M, Lowe, Margaret M, Huang, Linglin, Delaney, Conor, Long, Jaclyn M, Fung, Megan E, Newcomer, Kathleen, Tsai, Katy K, Chow, Melissa, Guinn, Samantha, Kuchroo, Juhi R, Burke, Kelly P, Schenkel, Jason M, Rosenblum, Michael D, Daud, Adil I, Sharpe, Arlene H, and Singer, Meromit

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Cancer, Genetics, 2.1 Biological and endogenous factors, Aetiology, Adenocarcinoma, Animals, Biomarkers, Tumor, CD8-Positive T-Lymphocytes, Cell Line, Tumor, Colonic Neoplasms, Female, Humans, Melanoma, Mice, Mice, Inbred C57BL, Programmed Cell Death 1 Receptor, Receptors, Antigen, T-Cell, Single-Cell Analysis, Skin Neoplasms, Transcriptome, Medical and Health Sciences, Biomedical and clinical sciences, Health sciences
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.

Published
2021

3. Single-nucleus and spatial transcriptome profiling of pancreatic cancer identifies multicellular dynamics associated with neoadjuvant treatment

Author

Hwang, William L., Jagadeesh, Karthik A., Guo, Jimmy A., Hoffman, Hannah I., Yadollahpour, Payman, Reeves, Jason W., Mohan, Rahul, Drokhlyansky, Eugene, Van Wittenberghe, Nicholas, Ashenberg, Orr, Farhi, Samouil L., Schapiro, Denis, Divakar, Prajan, Miller, Eric, Zollinger, Daniel R., Eng, George, Schenkel, Jason M., Su, Jennifer, Shiau, Carina, Yu, Patrick, Freed-Pastor, William A., Abbondanza, Domenic, Mehta, Arnav, Gould, Joshua, Lambden, Conner, Porter, Caroline B. M., Tsankov, Alexander, Dionne, Danielle, Waldman, Julia, Cuoco, Michael S., Nguyen, Lan, Delorey, Toni, Phillips, Devan, Barth, Jaimie L., Kem, Marina, Rodrigues, Clifton, Ciprani, Debora, Roldan, Jorge, Zelga, Piotr, Jorgji, Vjola, Chen, Jonathan H., Ely, Zackery, Zhao, Daniel, Fuhrman, Kit, Fropf, Robin, Beechem, Joseph M., Loeffler, Jay S., Ryan, David P., Weekes, Colin D., Ferrone, Cristina R., Qadan, Motaz, Aryee, Martin J., Jain, Rakesh K., Neuberg, Donna S., Wo, Jennifer Y., Hong, Theodore S., Xavier, Ramnik, Aguirre, Andrew J., Rozenblatt-Rosen, Orit, Mino-Kenudson, Mari, Castillo, Carlos Fernandez-del, Liss, Andrew S., Ting, David T., Jacks, Tyler, and Regev, Aviv

Published
2022
Full Text
View/download PDF

4. Deciphering the immunopeptidome in vivo reveals new tumour antigens

Author

Jaeger, Alex M., Stopfer, Lauren E., Ahn, Ryuhjin, Sanders, Emma A., Sandel, Demi A., Freed-Pastor, William A., Rideout, III, William M., Naranjo, Santiago, Fessenden, Tim, Nguyen, Kim B., Winter, Peter S., Kohn, Ryan E., Westcott, Peter M. K., Schenkel, Jason M., Shanahan, Sean-Luc, Shalek, Alex K., Spranger, Stefani, White, Forest M., and Jacks, Tyler

Published
2022
Full Text
View/download PDF

6. Intratumoral injection of the seasonal flu shot converts immunologically cold tumors to hot and serves as an immunotherapy for cancer

Author

Newman, Jenna H., Chesson, C. Brent, Herzog, Nora L., Bommareddy, Praveen K., Aspromonte, Salvatore M., Pepe, Russell, Estupinian, Ricardo, Aboelatta, Mones M., Buddhadev, Stuti, Tarabichi, Saeed, Lee, Michael, Li, Shengguo, Medina, Daniel J., Giurini, Eileena F., Gupta, Kajal H., Guevara-Aleman, Gabriel, Rossi, Marco, Nowicki, Christina, Abed, Abdulkareem, Goldufsky, Josef W., Broucek, Joseph R., Redondo, Raquel E., Rotter, David, Jhawar, Sachin R., Wang, Shang-Jui, Kohlhapp, Frederick J., Kaufman, Howard L., Thomas, Paul G., Gupta, Vineet, Kuzel, Timothy M., Reiser, Jochen, Paras, Joyce, Kane, Michael P., Singer, Eric A., Malhotra, Jyoti, Denzin, Lisa K., Sant’Angelo, Derek B., Rabson, Arnold B., Lee, Leonard Y., Lasfar, Ahmed, Langenfeld, John, Schenkel, Jason M., Fidler, Mary Jo, Ruiz, Emily S., Marzo, Amanda L., Rudra, Jai S., Silk, Ann W., and Zloza, Andrew

Published
2020

9. Plateletpheresis-associated lymphopenia in frequent platelet donors

Author

Gansner, John M., Rahmani, Mahboubeh, Jonsson, A. Helena, Fortin, Brooke M., Brimah, Idayat, Ellis, Martha, Smeland-Wagman, Robin, Li, Zhihan J., Schenkel, Jason M., Brenner, Michael B., Yefidoff-Freedman, Revital, Sloan, Steven R., Berliner, Nancy, Issa, Nicolas C., Baden, Lindsey R., Longo, Dan L., Wesemann, Duane R., Neuberg, Donna, Rao, Deepak A., and Kaufman, Richard M.

Published
2019
Full Text
View/download PDF

10. Sensing and alarm function of vaccine-elicited SIV-gag specific CD8 TRM in the reproductive mucosa of rhesus macaques

Author

Joag, Vineet, primary, Bimber, Benjamin, additional, Quarnstrom, Clare, additional, Bollimpelli, Venkata Satish, additional, Schenkel, Jason M, additional, Bertogliat, Mario, additional, O’Flanagan, Stephen, additional, Soerens, Andrew, additional, Stolley, Michael, additional, Hunter, Eric, additional, Amara, Rama Rao, additional, and Masopust, David, additional

Published
2023
Full Text
View/download PDF

13. Tissue-resident memory T cells trigger rapid exudation and local antibody accumulation

Author

Rosato, Pamela C., primary, Lotfi-Emran, Sahar, additional, Joag, Vineet, additional, Wijeyesinghe, Sathi, additional, Quarnstrom, Clare F., additional, Degefu, Hanna N., additional, Nedellec, Rebecca, additional, Schenkel, Jason M., additional, Beura, Lalit K., additional, Hangartner, Lars, additional, Burton, Dennis R., additional, and Masopust, David, additional

Published
2023
Full Text
View/download PDF

14. Therapeutic avenues for cancer neuroscience: translational frontiers and clinical opportunities

Author

Massachusetts Institute of Technology. Department of Biology, Koch Institute for Integrative Cancer Research at MIT, Harvard University--MIT Division of Health Sciences and Technology, Shi, Diana D, Guo, Jimmy A, Hoffman, Hannah I, Su, Jennifer, Mino-Kenudson, Mari, Barth, Jaimie L, Schenkel, Jason M, Loeffler, Jay S, Shih, Helen A, Hong, Theodore S, Wo, Jennifer Y, Aguirre, Andrew J, Jacks, Tyler, Zheng, Lei, Wen, Patrick Y, Wang, Timothy C, Hwang, William L, Massachusetts Institute of Technology. Department of Biology, Koch Institute for Integrative Cancer Research at MIT, Harvard University--MIT Division of Health Sciences and Technology, Shi, Diana D, Guo, Jimmy A, Hoffman, Hannah I, Su, Jennifer, Mino-Kenudson, Mari, Barth, Jaimie L, Schenkel, Jason M, Loeffler, Jay S, Shih, Helen A, Hong, Theodore S, Wo, Jennifer Y, Aguirre, Andrew J, Jacks, Tyler, Zheng, Lei, Wen, Patrick Y, Wang, Timothy C, and Hwang, William L

Abstract

With increasing attention on the essential roles of the tumour microenvironment in recent years, the nervous system has emerged as a novel and crucial facilitator of cancer growth. In this Review, we describe the foundational, translational, and clinical advances illustrating how nerves contribute to tumour proliferation, stress adaptation, immunomodulation, metastasis, electrical hyperactivity and seizures, and neuropathic pain. Collectively, this expanding knowledge base reveals multiple therapeutic avenues for cancer neuroscience that warrant further exploration in clinical studies. We discuss the available clinical data, including ongoing trials investigating novel agents targeting the tumour-nerve axis, and the therapeutic potential for repurposing existing neuroactive drugs as an anti-cancer approach, particularly in combination with established treatment regimens. Lastly, we discuss the clinical challenges of these treatment strategies and highlight unanswered questions and future directions in the burgeoning field of cancer neuroscience.

Published
2023

15. Deciphering the immunopeptidome in vivo reveals new tumour antigens

Author

Jaeger, Alex M., Stopfer, Lauren E., Ahn, Ryuhjin, Sanders, Emma A., Sandel, Demi A., Freed-Pastor, William A., Rideout, William M., Naranjo, Santiago, Fessenden, Tim, Nguyen, Kim B., Winter, Peter S., Kohn, Ryan E., Westcott, Peter M. K., Schenkel, Jason M., Shanahan, Sean-Luc, Shalek, Alex K., Spranger, Stefani, White, Forest M., and Jacks, Tyler

Abstract

Immunosurveillance of cancer requires the presentation of peptide antigens on major histocompatibility complex class I (MHC-I) molecules1–5. Current approaches to profiling of MHC-I-associated peptides, collectively known as the immunopeptidome, are limited to in vitro investigation or bulk tumour lysates, which limits our understanding of cancer-specific patterns of antigen presentation in vivo6. To overcome these limitations, we engineered an inducible affinity tag into the mouse MHC-I gene (H2-K1) and targeted this allele to the KrasLSL-G12D/+Trp53fl/flmouse model (KP/KbStrep)7. This approach enabled us to precisely isolate MHC-I peptides from autochthonous pancreatic ductal adenocarcinoma and from lung adenocarcinoma (LUAD) in vivo. In addition, we profiled the LUAD immunopeptidome from the alveolar type 2 cell of origin up to late-stage disease. Differential peptide presentation in LUAD was not predictable by mRNA expression or translation efficiency and is probably driven by post-translational mechanisms. Vaccination with peptides presented by LUAD in vivo induced CD8+T cell responses in naive mice and tumour-bearing mice. Many peptides specific to LUAD, including immunogenic peptides, exhibited minimal expression of the cognate mRNA, which prompts the reconsideration of antigen prediction pipelines that triage peptides according to transcript abundance8. Beyond cancer, the KbStrepallele is compatible with other Cre-driver lines to explore antigen presentation in vivo in the pursuit of understanding basic immunology, infectious disease and autoimmunity.

Published
2024
Full Text
View/download PDF

16. Modeling diverse genetic subtypes of lung adenocarcinoma with a next-generation alveolar type 2 organoid platform

Author

Naranjo, Santiago, primary, Cabana, Christina M., additional, LaFave, Lindsay M., additional, Romero, Rodrigo, additional, Shanahan, Sean-Luc, additional, Bhutkar, Arjun, additional, Westcott, Peter M.K., additional, Schenkel, Jason M., additional, Ghosh, Arkopravo, additional, Liao, Laura Z., additional, Del Priore, Isabella, additional, Yang, Dian, additional, and Jacks, Tyler, additional

Published
2022
Full Text
View/download PDF

18. Normalizing the environment recapitulates adult human immune traits in laboratory mice

Author

Beura, Lalit K., Hamilton, Sara E., Bi, Kevin, Schenkel, Jason M., Odumade, Oludare A., Casey, Kerry A., Thompson, Emily A., Fraser, Kathryn A., Rosato, Pamela C., Filali-Mouhim, Ali, Sekaly, Rafick P., Jenkins, Marc K., Vezys, Vaiva, Haining, W. Nicholas, Jameson, Stephen C., and Masopust, David

Subjects
T cells -- Physiological aspects, Physiological research, Immunity -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Our current understanding of immunology was largely defined in laboratory mice, partly because they are inbred and genetically homogeneous, can be genetically manipulated, allow kinetic tissue analyses to be carried out from the onset of disease, and permit the use of tractable disease models. Comparably reductionist experiments are neither technically nor ethically possible in humans. However, there is growing concern that laboratory mice do not reflect relevant aspects of the human immune system, which may account for failures to translate disease treatments from bench to bedside (1-8). Laboratory mice live in abnormally hygienic specific pathogen free (SPF) barrier facilities. Here we show that standard laboratory mouse husbandry has profound effects on the immune system and that environmental changes produce mice with immune systems closer to those of adult humans. Laboratory mice--like newborn, but not adult, humans--lack effector-differentiated and mucosally distributed memory T cells. These cell populations were present in free-living barn populations of feral mice and pet store mice with diverse microbial experience, and were induced in laboratory mice after co-housing with pet store mice, suggesting that the environment is involved in the induction of these cells. Altering the living conditions of mice profoundly affected the cellular composition of the innate and adaptive immune systems, resulted in global changes in blood cell gene expression to patterns that more closely reflected the immune signatures of adult humans rather than neonates, altered resistance to infection, and influenced T-cell differentiation in response to a de novo viral infection. These data highlight the effects of environment on the basal immune state and response to infection and suggest that restoring physiological microbial exposure in laboratory mice could provide a relevant tool for modelling immunological events in free-living organisms, including humans., Given reported species-specific differences in immune responses (1-8), we compared the distribution and differentiation of memory [CD8.sup.+] T cells between mice and humans. [CD8.sup.+] T cells are crucial for adaptive [...]

Published
2016

19. Sensing and alarm function of vaccine-elicited SIV-gag specific CD8 TRM in the reproductive mucosa of rhesus macaques

Author

Joag, Vineet, primary, Quarnstrom, Clare, additional, Soerens, Andrew, additional, Stolley, James Michael, additional, Schenkel, Jason M, additional, Fraser, Kathryn, additional, Vezys, Vaiva, additional, Skinner, Pamela J, additional, Hunter, Eric, additional, Bimber, Benjamin, additional, Amara, Rama Rao, additional, and Masopust, David, additional

Published
2022
Full Text
View/download PDF

20. Conventional type I dendritic cells maintain a reservoir of proliferative tumor-antigen specific TCF-1+ CD8+ T cells in tumor-draining lymph nodes

Author

Massachusetts Institute of Technology. Department of Biology, Schenkel, Jason M, Herbst, Rebecca H, Canner, David, Li, Amy, Hillman, Michelle, Shanahan, Sean-Luc, Gibbons, Grace, Smith, Olivia C, Kim, Jonathan Y, Westcott, Peter, Hwang, William L, Freed-Pastor, William A, Eng, George, Cuoco, Michael S, Rogers, Patricia, Park, Jin K, Burger, Megan L, Rozenblatt-Rosen, Orit, Cong, Le, Pauken, Kristen E, Regev, Aviv, Jacks, Tyler, Massachusetts Institute of Technology. Department of Biology, Schenkel, Jason M, Herbst, Rebecca H, Canner, David, Li, Amy, Hillman, Michelle, Shanahan, Sean-Luc, Gibbons, Grace, Smith, Olivia C, Kim, Jonathan Y, Westcott, Peter, Hwang, William L, Freed-Pastor, William A, Eng, George, Cuoco, Michael S, Rogers, Patricia, Park, Jin K, Burger, Megan L, Rozenblatt-Rosen, Orit, Cong, Le, Pauken, Kristen E, Regev, Aviv, and Jacks, Tyler

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.

Published
2022

21. Antigen dominance hierarchies shape TCF1+ progenitor CD8 T cell phenotypes in tumors

Author

Massachusetts Institute of Technology. Department of Biology, Burger, Megan L, Cruz, Amanda M, Crossland, Grace E, Gaglia, Giorgio, Ritch, Cecily C, Blatt, Sarah E, Bhutkar, Arjun, Canner, David, Kienka, Tamina, Tavana, Sara Z, Barandiaran, Alexia L, Garmilla, Andrea, Schenkel, Jason M, Hillman, Michelle, de los Rios Kobara, Izumi, Li, Amy, Jaeger, Alex M, Hwang, William L, Westcott, Peter MK, Manos, Michael P, Holovatska, Marta M, Hodi, F Stephen, Regev, Aviv, Santagata, Sandro, Jacks, Tyler, Massachusetts Institute of Technology. Department of Biology, Burger, Megan L, Cruz, Amanda M, Crossland, Grace E, Gaglia, Giorgio, Ritch, Cecily C, Blatt, Sarah E, Bhutkar, Arjun, Canner, David, Kienka, Tamina, Tavana, Sara Z, Barandiaran, Alexia L, Garmilla, Andrea, Schenkel, Jason M, Hillman, Michelle, de los Rios Kobara, Izumi, Li, Amy, Jaeger, Alex M, Hwang, William L, Westcott, Peter MK, Manos, Michael P, Holovatska, Marta M, Hodi, F Stephen, Regev, Aviv, Santagata, Sandro, and Jacks, Tyler

Abstract

CD8 T cell responses against different tumor neoantigens occur simultaneously, yet little is known about the interplay between responses and its impact on T cell function and tumor control. In mouse lung adenocarcinoma, we found that immunodominance is established in tumors, wherein CD8 T cell expansion is predominantly driven by the antigen that most stably binds MHC. T cells responding to subdominant antigens were enriched for a TCF1+ progenitor phenotype correlated with response to immune checkpoint blockade (ICB) therapy. However, the subdominant T cell response did not preferentially benefit from ICB due to a dysfunctional subset of TCF1+ cells marked by CCR6 and Tc17 differentiation. Analysis of human samples and sequencing datasets revealed that CCR6+ TCF1+ cells exist across human cancers and are not correlated with ICB response. Vaccination eliminated CCR6+ TCF1+ cells and dramatically improved the subdominant response, highlighting a strategy to optimally engage concurrent neoantigen responses against tumors.

Published
2022

22. The CD155/TIGIT axis promotes and maintains immune evasion in neoantigen-expressing pancreatic cancer

Author

Massachusetts Institute of Technology. Department of Biology, Freed-Pastor, William A, Lambert, Laurens J, Ely, Zackery A, Pattada, Nimisha B, Bhutkar, Arjun, Eng, George, Mercer, Kim L, Garcia, Ana P, Lin, Lin, Rideout, William M, Hwang, William L, Schenkel, Jason M, Jaeger, Alex M, Bronson, Roderick T, Westcott, Peter MK, Hether, Tyler D, Divakar, Prajan, Reeves, Jason W, Deshpande, Vikram, Delorey, Toni, Phillips, Devan, Yilmaz, Omer H, Regev, Aviv, Jacks, Tyler, Massachusetts Institute of Technology. Department of Biology, Freed-Pastor, William A, Lambert, Laurens J, Ely, Zackery A, Pattada, Nimisha B, Bhutkar, Arjun, Eng, George, Mercer, Kim L, Garcia, Ana P, Lin, Lin, Rideout, William M, Hwang, William L, Schenkel, Jason M, Jaeger, Alex M, Bronson, Roderick T, Westcott, Peter MK, Hether, Tyler D, Divakar, Prajan, Reeves, Jason W, Deshpande, Vikram, Delorey, Toni, Phillips, Devan, Yilmaz, Omer H, Regev, Aviv, and Jacks, Tyler

Abstract

The CD155/TIGIT axis can be co-opted during immune evasion in chronic viral infections and cancer. Pancreatic adenocarcinoma (PDAC) is a highly lethal malignancy, and immune-based strategies to combat this disease have been largely unsuccessful to date. We corroborate prior reports that a substantial portion of PDAC harbors predicted high-affinity MHC class I-restricted neoepitopes and extend these findings to advanced/metastatic disease. Using multiple preclinical models of neoantigen-expressing PDAC, we demonstrate that intratumoral neoantigen-specific CD8+ T cells adopt multiple states of dysfunction, resembling those in tumor-infiltrating lymphocytes of PDAC patients. Mechanistically, genetic and/or pharmacologic modulation of the CD155/TIGIT axis was sufficient to promote immune evasion in autochthonous neoantigen-expressing PDAC. Finally, we demonstrate that the CD155/TIGIT axis is critical in maintaining immune evasion in PDAC and uncover a combination immunotherapy (TIGIT/PD-1 co-blockade plus CD40 agonism) that elicits profound anti-tumor responses in preclinical models, now poised for clinical evaluation.

Published
2022

24. Modeling diverse genetic subtypes of lung adenocarcinoma with a next-generation alveolar type 2 organoid platform

Author

Naranjo, Santiago, primary, Cabana, Christina M., additional, LaFave, Lindsay M., additional, Westcott, Peter M.K., additional, Romero, Rodrigo, additional, Ghosh, Arkopravo, additional, Liao, Laura Z., additional, Schenkel, Jason M., additional, Priore, Isabella Del, additional, Bhutkar, Arjun, additional, Yang, Dian, additional, and Jacks, Tyler, additional

Published
2021
Full Text
View/download PDF

26. Conventional type I dendritic cells maintain a reservoir of proliferative tumor-antigen specific TCF-1+ CD8+ T cells in tumor-draining lymph nodes

Author

Schenkel, Jason M., primary, Herbst, Rebecca H., additional, Canner, David, additional, Li, Amy, additional, Hillman, Michelle, additional, Shanahan, Sean-Luc, additional, Gibbons, Grace, additional, Smith, Olivia C., additional, Kim, Jonathan Y., additional, Westcott, Peter, additional, Hwang, William L., additional, Freed-Pastor, William A., additional, Eng, George, additional, Cuoco, Michael S., additional, Rogers, Patricia, additional, Park, Jin K., additional, Burger, Megan L., additional, Rozenblatt-Rosen, Orit, additional, Cong, Le, additional, Pauken, Kristen E., additional, Regev, Aviv, additional, and Jacks, Tyler, additional

Published
2021
Full Text
View/download PDF

27. The CD155/TIGIT axis promotes and maintains immune evasion in neoantigen-expressing pancreatic cancer

Author

Freed-Pastor, William A., primary, Lambert, Laurens J., additional, Ely, Zackery A., additional, Pattada, Nimisha B., additional, Bhutkar, Arjun, additional, Eng, George, additional, Mercer, Kim L., additional, Garcia, Ana P., additional, Lin, Lin, additional, Rideout, William M., additional, Hwang, William L., additional, Schenkel, Jason M., additional, Jaeger, Alex M., additional, Bronson, Roderick T., additional, Westcott, Peter M.K., additional, Hether, Tyler D., additional, Divakar, Prajan, additional, Reeves, Jason W., additional, Deshpande, Vikram, additional, Delorey, Toni, additional, Phillips, Devan, additional, Yilmaz, Omer H., additional, Regev, Aviv, additional, and Jacks, Tyler, additional

Published
2021
Full Text
View/download PDF

28. Antigen dominance hierarchies shape TCF1+ progenitor CD8 T cell phenotypes in tumors

Author

Burger, Megan L., primary, Cruz, Amanda M., additional, Crossland, Grace E., additional, Gaglia, Giorgio, additional, Ritch, Cecily C., additional, Blatt, Sarah E., additional, Bhutkar, Arjun, additional, Canner, David, additional, Kienka, Tamina, additional, Tavana, Sara Z., additional, Barandiaran, Alexia L., additional, Garmilla, Andrea, additional, Schenkel, Jason M., additional, Hillman, Michelle, additional, de los Rios Kobara, Izumi, additional, Li, Amy, additional, Jaeger, Alex M., additional, Hwang, William L., additional, Westcott, Peter M.K., additional, Manos, Michael P., additional, Holovatska, Marta M., additional, Hodi, F. Stephen, additional, Regev, Aviv, additional, Santagata, Sandro, additional, and Jacks, Tyler, additional

Published
2021
Full Text
View/download PDF

32. Abstract 94: Multi-compartment reprogramming and spatially-resolved interactions in frozen pancreatic cancer with and without neoadjuvant chemotherapy and radiotherapy at single-cell resolution

Author

Hwang, William L., primary, Jagadeesh, Karthik A., additional, Guo, Jimmy A., additional, Hoffman, Hannah I., additional, Yadollahpour, Payman, additional, Reeves, Jason, additional, Drokhlyansky, Eugene, additional, Van Wittenberghe, Nicholas, additional, Farhi, Samouil, additional, Schapiro, Denis, additional, Eng, George, additional, Schenkel, Jason M., additional, Freed-Pastor, William A., additional, Ashenberg, Orr, additional, Rodrigues, Clifton, additional, Abbondanza, Domenic, additional, Delorey, Toni, additional, Phillips, Devan, additional, Roldan, Jorge, additional, Ciprani, Debora, additional, Kern, Marina, additional, Barth, Jaimie L., additional, Zollinger, Daniel R., additional, Fuhrman, Kit, additional, Fropf, Robin, additional, Beechem, Joseph, additional, Weekes, Colin, additional, Ferrone, Cristina R., additional, Wo, Jennifer Y., additional, Hong, Theodore S., additional, Rozenblatt-Rosen, Orit, additional, Aguirre, Andrew J., additional, Mino-Kenudson, Mari, additional, Fernandez-del- Castillo, Carlos, additional, Liss, Andrew S., additional, Ting, David T., additional, Jacks, Tyler, additional, and Regev, Aviv, additional

Published
2021
Full Text
View/download PDF

33. Single-cell analyses characterize circulating anti-tumor CD8+ T cells in mice and humans and identify markers for their enrichment

Author

Pauken, Kristen E, primary, Shahid, Osmaan, additional, Lagattuta, Kaitlyn A, additional, Mahuron, Kelly M, additional, Luber, Jacob M, additional, Lowe, Margaret M, additional, Huang, Linglin, additional, Delaney, Conor, additional, Long, Jaclyn, additional, Fung, Megan E, additional, Newcomer, Kathleen, additional, Tsai, Katy K, additional, Chow, Melissa, additional, Guinn, Samantha, additional, Kuchroo, Juhi R, additional, Burke, Kelly P, additional, Schenkel, Jason M, additional, Rosenblum, Michael D, additional, Daud, Adil I, additional, Sharpe, Arlene H, additional, and Singer, Meromit, additional

Published
2021
Full Text
View/download PDF

34. Nkg2d signaling on CD8+ T cells represses T-bet and rescues CD4-unhelped CD8+ T cell memory recall but not effector responses

Author

Kohlhapp, Frederick J., Zloza, Andrew, Schenkel, Jason M., Lyons, Gretchen E., Lacek, Andrew T., Moore, Tamson V., Varanasi, Vineeth, O'Sullivan, Jeremy A., Jagoda, Michael C., Williams, Jesse W., Marzo, Amanda L., Bellavance, Emily C., Zafirova, Biljana, Thomas, Paul G., Al-Harthi, Lena, Polic, Bojan, Sperling, Anne I., and Guevara-Patino, Jose A.

Subjects
T cells -- Receptors, Antigen receptors, T cell -- Physiological aspects -- Research, Immune response -- Physiological aspects -- Research, Cellular signal transduction -- Physiological aspects -- Research, Biological sciences, Health
Abstract

CD4-unhelped CD8+ T cells are functionally defective T cells primed in the absence of CD4+ T cell help. Given the co-stimulatory role of natural-killer group 2, member D protein (NKG2D) on CD8+ T cells, we investigated its ability to rescue these immunologically impotent cells. We demonstrate that augmented co-stimulation through NKG2D during priming paradoxically rescues memory, but not effector, CD8+ T cell responses. NKG2D-mediated rescue is characterized by reversal of elevated transcription factor T-box expressed in T cells (T-bet) expression and recovery of interleukin-2 and interferon-g production and cytolytic responses. Rescue is abrogated in CD8+ T cells lacking NKG2D. Augmented co-stimulation through NKG2D confers a high rate of survival to mice lacking CD4+ T cells in a CD4-dependent influenza model and rescues HIV-specific CD8+ T cell responses from CD4-deficient HIV-positive donors. These findings demonstrate that augmented co-stimulation through NKG2D is effective in rescuing CD4-unhelped CD8+T cells from their pathophysiological fate and may provide therapeutic benefits., Memory CD8+ T cells confer efficient and long-lasting immunity against secondary pathogen exposure(1,2). Events during primary expo-sure (priming) affect the quality of the initial effector and subsequent memory cytotoxic T [...]

Published
2012
Full Text
View/download PDF

37. Abstract PO016: Single-cell analyses characterize circulating anti-tumor CD8 T cells and identify markers for their isolation

Author

Pauken, Kristen E., primary, Shahid, Osmaan, additional, Lagattuta, Kaitlyn A., additional, Mahuron, Kelly M., additional, Luber, Jacob M., additional, Lowe, Margaret M., additional, Huang, Linglin, additional, Delaney, Conor, additional, Long, Jaclyn M., additional, Fung, Megan E., additional, Newcomer, Kathleen, additional, Tsai, Katy K., additional, Chow, Melissa, additional, Guinn, Samantha, additional, Kuchroo, Juhi R., additional, Burke, Kelly P., additional, Schenkel, Jason M., additional, Rosenblum, Michael D., additional, Daud, Adil I., additional, Sharpe, Arlene H., additional, and Singer, Meromit, additional

Published
2021
Full Text
View/download PDF

38. T-cell invigoration to tumour burden ratio associated with anti-PD-1 response

Author

Huang, Alexander C., Postow, Michael A., Orlowski, Robert J., Mick, Rosemarie, Bengsch, Bertram, Manne, Sasikanth, Xu, Wei, Harmon, Shannon, Giles, Josephine R., Wenz, Brandon, Adamow, Matthew, Kuk, Deborah, Panageas, Katherine S., Carrera, Cristina, Wong, Phillip, Quagliarello, Felix, Wubbenhorst, Bradley, DAndrea, Kurt, Pauken, Kristen E., Herati, Ramin S., Staupe, Ryan P., Schenkel, Jason M., McGettigan, Suzanne, Kothari, Shawn, George, Sangeeth M., Vonderheide, Robert H., Amaravadi, Ravi K., Karakousis, Giorgos C., Schuchter, Lynn M., Xu, Xiaowei, Nathanson, Katherine L., Wolchok, Jedd D., Gangadhar, Tara C., and Wherry, E. John

Subjects
Apoptosis -- Research, Cancer research, Tumors -- Physiological aspects, Melanoma -- Physiological aspects, T cells -- Physiological aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
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[sub.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 T[sub.ex] 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., Author(s): Alexander C. Huang (corresponding author) [1, 2, 3, 4]; Michael A. Postow [5, 6]; Robert J. Orlowski [1, 2, 3, 4]; Rosemarie Mick [3, 4, 7]; Bertram Bengsch [2, [...]

Published
2017
Full Text
View/download PDF

39. CRISPR-mediated modeling and functional validation of candidate tumor suppressor genes in small cell lung cancer

Author

Massachusetts Institute of Technology. Department of Biology, Harvard University--MIT Division of Health Sciences and Technology, Koch Institute for Integrative Cancer Research at MIT, Ng, Sheng Rong, Rideout, William M., Akama-Garren, Elliot H., Bhutkar, Arjun, Mercer, Kim L., Schenkel, Jason M., Bronson, Roderick T., Jacks, Tyler E, Massachusetts Institute of Technology. Department of Biology, Harvard University--MIT Division of Health Sciences and Technology, Koch Institute for Integrative Cancer Research at MIT, Ng, Sheng Rong, Rideout, William M., Akama-Garren, Elliot H., Bhutkar, Arjun, Mercer, Kim L., Schenkel, Jason M., Bronson, Roderick T., and Jacks, Tyler E

Abstract

Small cell lung cancer (SCLC) is a highly aggressive subtype of lung cancer that remains among the most lethal of solid tumor malignancies. Recent genomic sequencing studies have identified many recurrently mutated genes in human SCLC tumors. However, the functional roles of most of these genes remain to be validated. Here, we have adapted the CRISPR-Cas9 system to a well-established murine model of SCLC to rapidly model loss-of-function mutations in candidate genes identified from SCLC sequencing studies. We show that loss of the gene p107 significantly accelerates tumor progression. Notably, compared with loss of the closely related gene p130, loss of p107 results in fewer but larger tumors as well as earlier metastatic spread. In addition, we observe differences in proliferation and apoptosis as well as altered distribution of initiated tumors in the lung, resulting from loss of p107 or p130. Collectively, these data demonstrate the feasibility of using the CRISPR-Cas9 system to model loss of candidate tumor suppressor genes in SCLC, and we anticipate that this approach will facilitate efforts to investigate mechanisms driving tumor progression in this deadly disease. Keywords: small cell lung cancer; CRISPR; GEMM, National Cancer Institute. Koch Institute Support (Grant P30-CA14051)

Published
2020

40. Inhibitory signaling sustains a distinct early memory CD8 + T cell precursor that is resistant to DNA damage

Author

Johnnidis, Jonathan B., primary, Muroyama, Yuki, additional, Ngiow, Shin Foong, additional, Chen, Zeyu, additional, Manne, Sasikanth, additional, Cai, Zhangying, additional, Song, Shufei, additional, Platt, Jesse M., additional, Schenkel, Jason M., additional, Abdel-Hakeem, Mohamed, additional, Beltra, Jean-Christophe, additional, Greenplate, Allison R., additional, Ali, Mohammed-Alkhatim A., additional, Nzingha, Kito, additional, Giles, Josephine R., additional, Harly, Christelle, additional, Attanasio, John, additional, Pauken, Kristen E., additional, Bengsch, Bertram, additional, Paley, Michael A., additional, Tomov, Vesselin T., additional, Kurachi, Makoto, additional, Vignali, Dario A. A., additional, Sharpe, Arlene H., additional, Reiner, Steven L., additional, Bhandoola, Avinash, additional, Johnson, F. Bradley, additional, and Wherry, E. John, additional

Published
2021
Full Text
View/download PDF

41. Abstract PR-007: Single-nucleus and spatial transcriptomics of archival pancreatic ductal adenocarcinoma reveals multi-compartment reprogramming after neoadjuvant treatment

Author

Hwang, William L., primary, Jagadeesh, Karthik A., additional, Guo, Jimmy A., additional, Hoffman, Hannah I., additional, Drokhlyansky, Eugene, additional, Van Wittenberghe, Nicholas, additional, Farhi, Samouil, additional, Schapiro, Denis, additional, Reeves, Jason, additional, Zollinger, Daniel R., additional, Eng, George, additional, Schenkel, Jason M., additional, Freed-Pastor, William A., additional, Rodrigues, Clifton, additional, Abbondanza, Domenic, additional, Ciprani, Debora, additional, Wo, Jennifer Y., additional, Hong, Theodore S., additional, Aguirre, Andrew J., additional, Rozenblatt-Rosen, Orit, additional, Mino-Kenudson, Mari, additional, Fernandez-del Castillo, Carlos, additional, Liss, Andrew S., additional, Jacks, Tyler E., additional, and Regev, Aviv, additional

Published
2020
Full Text
View/download PDF

43. Single-cell analyses identify circulating anti-tumor CD8 T cells and markers for their enrichment

Author

Pauken, Kristen E., primary, Shahid, Osmaan, additional, Lagattuta, Kaitlyn A., additional, Mahuron, Kelly M., additional, Luber, Jacob M., additional, Lowe, Margaret M., additional, Huang, Linglin, additional, Delaney, Conor, additional, Long, Jaclyn M., additional, Fung, Megan E., additional, Newcomer, Kathleen, additional, Tsai, Katy K., additional, Chow, Melissa, additional, Guinn, Samantha, additional, Kuchroo, Juhi R., additional, Burke, Kelly P., additional, Schenkel, Jason M., additional, Rosenblum, Michael D., additional, Daud, Adil I., additional, Sharpe, Arlene H., additional, and Singer, Meromit, additional

Published
2020
Full Text
View/download PDF

44. Single-nucleus and spatial transcriptomics of archival pancreatic cancer reveals multi-compartment reprogramming after neoadjuvant treatment

Author

Hwang, William L., primary, Jagadeesh, Karthik A., additional, Guo, Jimmy A., additional, Hoffman, Hannah I., additional, Yadollahpour, Payman, additional, Mohan, Rahul, additional, Drokhlyansky, Eugene, additional, Van Wittenberghe, Nicholas, additional, Ashenberg, Orr, additional, Farhi, Samouil, additional, Schapiro, Denis, additional, Reeves, Jason, additional, Zollinger, Daniel R., additional, Eng, George, additional, Schenkel, Jason M., additional, Freed-Pastor, William A., additional, Rodrigues, Clifton, additional, Gould, Joshua, additional, Lambden, Conner, additional, Porter, Caroline, additional, Tsankov, Alexander, additional, Dionne, Danielle, additional, Abbondanza, Domenic, additional, Waldman, Julia, additional, Cuoco, Michael, additional, Nguyen, Lan, additional, Delorey, Toni, additional, Phillips, Devan, additional, Ciprani, Debora, additional, Kern, Marina, additional, Mehta, Arnav, additional, Fuhrman, Kit, additional, Fropf, Robin, additional, Beechem, Joseph, additional, Loeffler, Jay S., additional, Ryan, David P., additional, Weekes, Colin D., additional, Ting, David T., additional, Ferrone, Cristina R., additional, Wo, Jennifer Y., additional, Hong, Theodore S., additional, Aguirre, Andrew J., additional, Rozenblatt-Rosen, Orit, additional, Mino-Kenudson, Mari, additional, Castillo, Carlos Fernandez-del, additional, Liss, Andrew S., additional, Jacks, Tyler, additional, and Regev, Aviv, additional

Published
2020
Full Text
View/download PDF

46. Intratumoral injection of the seasonal flu shot converts immunologically cold tumors to hot and serves as an immunotherapy for cancer

Author

Newman, Jenna H., primary, Chesson, C. Brent, additional, Herzog, Nora L., additional, Bommareddy, Praveen K., additional, Aspromonte, Salvatore M., additional, Pepe, Russell, additional, Estupinian, Ricardo, additional, Aboelatta, Mones M., additional, Buddhadev, Stuti, additional, Tarabichi, Saeed, additional, Lee, Michael, additional, Li, Shengguo, additional, Medina, Daniel J., additional, Giurini, Eileena F., additional, Gupta, Kajal H., additional, Guevara-Aleman, Gabriel, additional, Rossi, Marco, additional, Nowicki, Christina, additional, Abed, Abdulkareem, additional, Goldufsky, Josef W., additional, Broucek, Joseph R., additional, Redondo, Raquel E., additional, Rotter, David, additional, Jhawar, Sachin R., additional, Wang, Shang-Jui, additional, Kohlhapp, Frederick J., additional, Kaufman, Howard L., additional, Thomas, Paul G., additional, Gupta, Vineet, additional, Kuzel, Timothy M., additional, Reiser, Jochen, additional, Paras, Joyce, additional, Kane, Michael P., additional, Singer, Eric A., additional, Malhotra, Jyoti, additional, Denzin, Lisa K., additional, Sant’Angelo, Derek B., additional, Rabson, Arnold B., additional, Lee, Leonard Y., additional, Lasfar, Ahmed, additional, Langenfeld, John, additional, Schenkel, Jason M., additional, Fidler, Mary Jo, additional, Ruiz, Emily S., additional, Marzo, Amanda L., additional, Rudra, Jai S., additional, Silk, Ann W., additional, and Zloza, Andrew, additional

Published
2019
Full Text
View/download PDF

48. IL-33 Signaling Alters Regulatory T Cell Diversity in Support of Tumor Development

Author

Li, Amy, primary, Herbst, Rebecca H., additional, Canner, David, additional, Schenkel, Jason M., additional, Smith, Olivia C., additional, Kim, Jonathan Y., additional, Hillman, Michelle, additional, Bhutkar, Arjun, additional, Cuoco, Michael S., additional, Rappazzo, C. Garrett, additional, Rogers, Patricia, additional, Dang, Celeste, additional, Jerby-Arnon, Livnat, additional, Rozenblatt-Rosen, Orit, additional, Cong, Le, additional, Birnbaum, Michael, additional, Regev, Aviv, additional, and Jacks, Tyler, additional

Published
2019
Full Text
View/download PDF

49. Recapitulating adult human immune traits in laboratory mice by normalizing environment

Author

Beura, Lalit K., Hamilton, Sara E., Bi, Kevin, Schenkel, Jason M., Odumade, Oludare A., Casey, Kerry A., Thompson, Emily A., Fraser, Kathryn A., Rosato, Pamela C., Filali-Mouhim, Ali, Sekaly, Rafick P., Jenkins, Marc K., Vezys, Vaiva, Haining, W. Nicholas, Jameson, Stephen C., and Masopust, David

Subjects
Mice, Immune System, Animals, Humans, Article
Abstract

Our current understanding of immunology was largely defined in laboratory mice because of experimental advantages including inbred homogeneity, tools for genetic manipulation, the ability to perform kinetic tissue analyses starting with the onset of disease, and tractable models. Comparably reductionist experiments are neither technically nor ethically possible in humans. Despite revealing many fundamental principals of immunology, there is growing concern that mice fail to capture relevant aspects of the human immune system, which may account for failures to translate disease treatments from bench to bedside1–8. Laboratory mice live in abnormally hygienic “specific pathogen free” (SPF) barrier facilities. Here we show that the standard practice of laboratory mouse husbandry has profound effects on the immune system and that environmental changes result in better recapitulation of features of adult humans. Laboratory mice lack effector-differentiated and mucosally distributed memory T cells, which more closely resembles neonatal than adult humans. These cell populations were present in free-living barn populations of feral mice, pet store mice with diverse microbial experience, and were induced in laboratory mice after co-housing with pet store mice, suggesting a role for environment. Consequences of altering mouse housing profoundly impacted the cellular composition of the innate and adaptive immune system and resulted in global changes in blood cell gene expression patterns that more closely aligned with immune signatures of adult humans rather than neonates, altered the mouse’s resistance to infection, and impacted T cell differentiation to a de novo viral infection. These data highlight the impact of environment on the basal immune state and response to infection and suggest that restoring physiological microbial exposure in laboratory mice could provide a relevant tool for modeling immunological events in free-living organisms, including humans.

Published
2016

Catalog

Books, media, physical & digital resources
See catalog results