基本信息
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职业迁徙
个人简介
Research Interests
T Cell Exhaustion, Immunotherapy, T Cell Memory, Viral Immunity, Immune Oncology, Immune Health.
Key words:
T cell exhaustion, PD-1, T cell memory, Chronic infection, Cancer Immunotherapy, Checkpoint Blockade, Memory T cell differentiation, T Follicular Helper Cells.
Research Summary
A major goal of the research the Wherry laboratory is to understand the fundamental biology of T cell exhaustion during chronic infections and cancer. Our work has defined the nature of T cell exhaustion including altered function, limited responses to antigen restimulation, high co-expression of inhibitory receptors such as PD-1, and a characteristically distinct transcriptional program. We have defined the importance of limited protective capacity of these cells during infection and cancer and have also uncovered the pathways involved in re-invigorating these cells by checkpoint blockade. We have identified subsets of exhausted T cells with different functions and reinvigoration potential and delineated the developmental relationships between these subsets. We have also found a major mechanism limiting responses of exhausted T cells. By profiling the open chromatin landscape of exhausted CD8 T cells we found that these cells were completely distinct from effector and memory CD8 T cells. Moreover, this epigenetic landscape did not change upon checkpoint blockade resulting in a reversion to exhaustion after transient benefit. These data identified exhausted T cells as a distinct immune lineage separate from effector and memory CD8 T cells. Our work has also now discovered the lineage programmer of exhausted CD8 T cells call Tox, an HMG transcription factor that induces the epigenetic changes associated with CD8 T cell exhaustion. Ongoing work continues to interrogate the mechanisms of Tox and other regulators of exhausted T cell formation, regulation and reversibility.
A second major focus in the lab is to use knowledge of fundamental immune biology, including of exhausted T cells, but also follicular helper T cells and B cells, to perform high dimensional immune profiling in human disease. We have applied these approaches to immune oncology where we first identified exhausted T cells as the major responding cell type in human cancer patients receiving PD-1 blockade treatment. We have also applied these approaches to understanding the combination of checkpoint blockade and radiation in cancer, HIV infection, human influenza virus vaccination, human immune cell migration, and pediatric respiratory infections. Our goal is to use such approaches to define the baseline, and disease associated, features of overall Immune Health and use this information to interrogate individual responses to therapeutic interventions.
Overall, our laboratory uses many high dimensional immune profiling approaches, genomics including RNA-seq, scRNA-seq, ATA-seq, scATAC-seq, other epigenetic profiling approaches, high dimensional imaging (CODEX) and rests on a strong foundation of computational biology and informatics.
T Cell Exhaustion, Immunotherapy, T Cell Memory, Viral Immunity, Immune Oncology, Immune Health.
Key words:
T cell exhaustion, PD-1, T cell memory, Chronic infection, Cancer Immunotherapy, Checkpoint Blockade, Memory T cell differentiation, T Follicular Helper Cells.
Research Summary
A major goal of the research the Wherry laboratory is to understand the fundamental biology of T cell exhaustion during chronic infections and cancer. Our work has defined the nature of T cell exhaustion including altered function, limited responses to antigen restimulation, high co-expression of inhibitory receptors such as PD-1, and a characteristically distinct transcriptional program. We have defined the importance of limited protective capacity of these cells during infection and cancer and have also uncovered the pathways involved in re-invigorating these cells by checkpoint blockade. We have identified subsets of exhausted T cells with different functions and reinvigoration potential and delineated the developmental relationships between these subsets. We have also found a major mechanism limiting responses of exhausted T cells. By profiling the open chromatin landscape of exhausted CD8 T cells we found that these cells were completely distinct from effector and memory CD8 T cells. Moreover, this epigenetic landscape did not change upon checkpoint blockade resulting in a reversion to exhaustion after transient benefit. These data identified exhausted T cells as a distinct immune lineage separate from effector and memory CD8 T cells. Our work has also now discovered the lineage programmer of exhausted CD8 T cells call Tox, an HMG transcription factor that induces the epigenetic changes associated with CD8 T cell exhaustion. Ongoing work continues to interrogate the mechanisms of Tox and other regulators of exhausted T cell formation, regulation and reversibility.
A second major focus in the lab is to use knowledge of fundamental immune biology, including of exhausted T cells, but also follicular helper T cells and B cells, to perform high dimensional immune profiling in human disease. We have applied these approaches to immune oncology where we first identified exhausted T cells as the major responding cell type in human cancer patients receiving PD-1 blockade treatment. We have also applied these approaches to understanding the combination of checkpoint blockade and radiation in cancer, HIV infection, human influenza virus vaccination, human immune cell migration, and pediatric respiratory infections. Our goal is to use such approaches to define the baseline, and disease associated, features of overall Immune Health and use this information to interrogate individual responses to therapeutic interventions.
Overall, our laboratory uses many high dimensional immune profiling approaches, genomics including RNA-seq, scRNA-seq, ATA-seq, scATAC-seq, other epigenetic profiling approaches, high dimensional imaging (CODEX) and rests on a strong foundation of computational biology and informatics.
研究兴趣
论文共 49 篇作者统计合作学者相似作者
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Jaesik Kim, Matei Ionita,Matthew Lee, Michelle L. McKeague,Ajinkya Pattekar,Mark M. Painter,Joost Wagenaar, Van Truong, Dylan T. Norton,Divij Mathew,Yonghyun Nam,Sokratis A. Apostolidis,
biorxiv(2024)
Thomas M Anderson,Bryan H Chang, Alexander C Huang,Xiaowei Xu, Daniel Yoon, Catherine G Shang,Rosemarie Mick,Erin Schubert,Suzanne McGettigan, Kristin Kreider,Wei Xu,E John Wherry,
Clinical cancer research : an official journal of the American Association for Cancer Researchpp.OF1-OF10, (2024)
Nature Immunologyno. 10 (2023): 1778-1778
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SCIENCE IMMUNOLOGYno. 90 (2023): eadh0687-eadh0687
Dana Pueschl,Derek A. Oldridge,Jonathan P. Belman, William F. Chandler,Anupma Nayak,Bradley Wubbenhorst,John Pluta,Michael Feldman,E. John Wherry,Heather Thorne,Georgia Chenevix‐Trench, Kathleen Cuningham Foundation Consortium for Resea kConFab,
Cancer Researchno. 7_Supplement (2023): 4648-4648
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bioRxiv : the preprint server for biology (2023)
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Amy E. Baxter,Hua Huang,Josephine R. Giles,Zeyu Chen,Jennifer E. Wu,Sydney Drury, Katherine Dalton,Simone L. Park, Leonel Torres, Brandon W. Simone,Max Klapholz,Shin Foong Ngiow,
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NATURE IMMUNOLOGY (2023)
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