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E. John Wherry, PhD
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Richard and Barbara Schiffrin President's Distinguished Professor
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Director, Institute for Immunology & Immune Health (I3H)
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Co-Director, Parker Institute for Cancer Immunotherapy at the University of Pennsylvania
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Chair, Department of Systems Pharmacology and Translational Therapeutics
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Co-Program Chair, Immunobiology Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia PA
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Department: Systems Pharmacology and Translational Therapeutics
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Graduate Group Affiliations
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Contact information
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421 Curie Blvd
36 BRB II/III Room 354
Philadelphia, PA 19104
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36 BRB II/III Room 354
Philadelphia, PA 19104
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Publications
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Education:
21 7 BS 14 (Science) c
36 Pennsylvania State University, 1993.
21 8 PhD 17 (Immunology) c
34 Thomas Jefferson University, 2000.
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Permanent link21 7 BS 14 (Science) c
36 Pennsylvania State University, 1993.
21 8 PhD 17 (Immunology) c
34 Thomas Jefferson University, 2000.
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6a T Cell Exhaustion, Immunotherapy, T Cell Memory, Viral Immunity, Immune Oncology, Immune Health.
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1a Key words:
a7 T cell exhaustion, PD-1, T cell memory, Chronic infection, Cancer Immunotherapy, Checkpoint Blockade, Memory T cell differentiation, T Follicular Helper Cells.
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1f Research Summary
649 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.
365 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.
127 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.
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24 Lab Rotation Projects
66 1) Immune regulation including checkpoint blockade during chronic viral infections and cancer
40 2) Transcriptional regulation of T cell differentiation
42 3) Immune profiling during human disease and intervention
2d 4) Epigenetics and immune regulation
37 5) In vivo CRISPR screening of T cell responses
5f 6) Immune engineering and synthetic biology to overcome or modulate T cell exhaustion.
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51 For scheduling, administrative and departmental issues please contact
50 Brady Galan, Executive Assistant - brady.galan@pennmedicine.upenn.edu
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3b For laboratory related questions, please contact
5a Christopher Holliday, Lab Manager - christopher.holliday@pennmedicine.upenn.edu
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1c Lab personnel
2e Victor Alcalde – Research Technician
2c Mohammad Ali – Research Specialist
2b Reid Banciella – Graduate Student
2d Jessica Barragan – Graduate Student
2e Trent Campos – Undergraduate Student
32 Maria Cardenas – Postdoctoral Researcher
2b Naomi Douek – Research Technician
36 Victoria Fang – Postdoctoral Fellow (MD/PhD)
3d Benjamin Fensterheim – Postdoctoral Fellow (MD/PhD)
2d Audrey Gang – Undergraduate Student
39 Jon Ghergurovich – Postdoctoral Fellow (MD/PhD)
38 Josephine Giles – Senior Research Investigator
38 Elliot Goepfert-Waterman – Research Technician
31 Sophie Gray-Gaillard – Graduate Student
26 Chris Holliday – Lab Manager
29 Hua Huang – Research Specialist
2e Jane Huang – Postdoctoral Researcher
32 Wumesh Kc – Postdoctoral Fellow (MD/PhD)
29 Max Klapholz – Graduate Student
38 Jonathan Kotzin – Postdoctoral Fellow (MD/PhD)
27 Mathew Lee – Graduate Student
29 Stefan Lundh – Graduate Student
2f Sasikanth Manne – Research Specialist
30 Divij Mathew – Postdoctoral Researcher
37 Brittney Newby – Postdoctoral Fellow (MD/PhD)
2e Shin Ngiow – Postdoctoral Researcher
30 Mark Painter – Postdoctoral Researcher
2f Simone Park – Postdoctoral Researcher
2b Matthew Sullivan – MD/PhD Student
2e Joseph Tandurella – Graduate Student
2b Leonel Torres – Graduate Student
27 Van Truong – Graduate Student
2c Ping Wang – Postdoctoral Researcher
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Description of Research Expertise
2b Research Interests6a T Cell Exhaustion, Immunotherapy, T Cell Memory, Viral Immunity, Immune Oncology, Immune Health.
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1a Key words:
a7 T cell exhaustion, PD-1, T cell memory, Chronic infection, Cancer Immunotherapy, Checkpoint Blockade, Memory T cell differentiation, T Follicular Helper Cells.
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1f Research Summary
649 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.
365 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.
127 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.
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24 Lab Rotation Projects
66 1) Immune regulation including checkpoint blockade during chronic viral infections and cancer
40 2) Transcriptional regulation of T cell differentiation
42 3) Immune profiling during human disease and intervention
2d 4) Epigenetics and immune regulation
37 5) In vivo CRISPR screening of T cell responses
5f 6) Immune engineering and synthetic biology to overcome or modulate T cell exhaustion.
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51 For scheduling, administrative and departmental issues please contact
50 Brady Galan, Executive Assistant - brady.galan@pennmedicine.upenn.edu
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3b For laboratory related questions, please contact
5a Christopher Holliday, Lab Manager - christopher.holliday@pennmedicine.upenn.edu
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1c Lab personnel
2e Victor Alcalde – Research Technician
2c Mohammad Ali – Research Specialist
2b Reid Banciella – Graduate Student
2d Jessica Barragan – Graduate Student
2e Trent Campos – Undergraduate Student
32 Maria Cardenas – Postdoctoral Researcher
2b Naomi Douek – Research Technician
36 Victoria Fang – Postdoctoral Fellow (MD/PhD)
3d Benjamin Fensterheim – Postdoctoral Fellow (MD/PhD)
2d Audrey Gang – Undergraduate Student
39 Jon Ghergurovich – Postdoctoral Fellow (MD/PhD)
38 Josephine Giles – Senior Research Investigator
38 Elliot Goepfert-Waterman – Research Technician
31 Sophie Gray-Gaillard – Graduate Student
26 Chris Holliday – Lab Manager
29 Hua Huang – Research Specialist
2e Jane Huang – Postdoctoral Researcher
32 Wumesh Kc – Postdoctoral Fellow (MD/PhD)
29 Max Klapholz – Graduate Student
38 Jonathan Kotzin – Postdoctoral Fellow (MD/PhD)
27 Mathew Lee – Graduate Student
29 Stefan Lundh – Graduate Student
2f Sasikanth Manne – Research Specialist
30 Divij Mathew – Postdoctoral Researcher
37 Brittney Newby – Postdoctoral Fellow (MD/PhD)
2e Shin Ngiow – Postdoctoral Researcher
30 Mark Painter – Postdoctoral Researcher
2f Simone Park – Postdoctoral Researcher
2b Matthew Sullivan – MD/PhD Student
2e Joseph Tandurella – Graduate Student
2b Leonel Torres – Graduate Student
27 Van Truong – Graduate Student
2c Ping Wang – Postdoctoral Researcher
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137 Paley, M.A., Kroy, D.C., Dolfi, D.V., Bikoff, E., Robertson, E.J., Lauer, G.M., Reiner, S.L, Wherry, E.J. : Progenitor and terminal subsets of CD8+ T cells cooperate to contain chronic viral infection. Science 338(6111): 1220-5, Nov 2012.
127 Doering, T.A., Crawfod, A., Angelosanto, J.M., Paley, M.A., Wherry, E.J.: Network analysis reveals centrally connected genes and pathways involved in CD8+ T cell exhaustion versus memory. Immunity 37(6): 1130-44, Dec 2012.
124 Odorizzi PM, Pauken, KE, Paley MA, Sharpe A and Wherry EJ.: Genetic absence of PD-1 promotes accumulation of terminally differentiated exhausted CD8+ T cells. Journal of Experimental Medicine 212(7): 1125-37, June 2015.
d3 Wherry E John, Kurachi Makoto: Molecular and cellular insights into T cell exhaustion. Nature reviews. Immunology 15(8): 486-99, Aug 2015.
1b8 Bengsch Bertram, Johnson Andy L, Kurachi Makoto, Odorizzi Pamela M, Pauken Kristen E, Attanasio John, Stelekati Erietta, McLane Laura M, Paley Michael A, Delgoffe Greg M, Wherry E John: Bioenergetic Insufficiencies Due to Metabolic Alterations Regulated by the Inhibitory Receptor PD-1 Are an Early Driver of CD8(+) T Cell Exhaustion. Immunity 45(2): 358-73, 08 2016.
21a Pauken Kristen E, Sammons Morgan A, Odorizzi Pamela M, Manne Sasikanth, Godec Jernej, Khan Omar, Drake Adam M, Chen Zeyu, Sen Debattama R, Kurachi Makoto, Barnitz R Anthony, Bartman Caroline, Bengsch Bertram, Huang Alexander C, Schenkel Jason M, Vahedi Golnaz, Haining W Nicholas, Berger Shelley L, Wherry E John: Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science (New York, N.Y.) 354(6316): 1160-1165, 12 2016.
304 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, D'Andrea 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, Wherry E John: T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature 545(7652): 60-65, 05 2017.
184 Kurachi Makoto, Kurachi Junko, Chen Zeyu, Johnson John, Khan Omar, Bengsch Bertram, Stelekati Erietta, Attanasio John, McLane Laura M, Tomura Michio, Ueha Satoshi, Wherry E John: Optimized retroviral transduction of mouse T cells for in vivo assessment of gene function. Nature protocols 12(9): 1980-1998, Sep 2017.
1d8 Tomov Vesselin T, Palko Olesya, Lau Chi Wai, Pattekar Ajinkya, Sun Yuhang, Tacheva Ralitza, Bengsch Bertram, Manne Sasikanth, Cosma Gabriela L, Eisenlohr Laurence C, Nice Timothy J, Virgin Herbert W, Wherry E John: Differentiation and Protective Capacity of Virus-Specific CD8+ T Cells Suggest Murine Norovirus Persistence in an Immune-Privileged Enteric Niche. Immunity 47(4): 723-738.e5, Oct 2017.
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Selected Publications
162 Blackburn, S.D., Shin, H., Haining, W.N., Zou, T., Workman, C.J., Polley, A., Betts, M.R., Freeman, G.J., Vignali, D.A.A., Wherry, E.J. : Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat. Immunol. 10(1): 29-37, Jan 2009.137 Paley, M.A., Kroy, D.C., Dolfi, D.V., Bikoff, E., Robertson, E.J., Lauer, G.M., Reiner, S.L, Wherry, E.J. : Progenitor and terminal subsets of CD8+ T cells cooperate to contain chronic viral infection. Science 338(6111): 1220-5, Nov 2012.
127 Doering, T.A., Crawfod, A., Angelosanto, J.M., Paley, M.A., Wherry, E.J.: Network analysis reveals centrally connected genes and pathways involved in CD8+ T cell exhaustion versus memory. Immunity 37(6): 1130-44, Dec 2012.
124 Odorizzi PM, Pauken, KE, Paley MA, Sharpe A and Wherry EJ.: Genetic absence of PD-1 promotes accumulation of terminally differentiated exhausted CD8+ T cells. Journal of Experimental Medicine 212(7): 1125-37, June 2015.
d3 Wherry E John, Kurachi Makoto: Molecular and cellular insights into T cell exhaustion. Nature reviews. Immunology 15(8): 486-99, Aug 2015.
1b8 Bengsch Bertram, Johnson Andy L, Kurachi Makoto, Odorizzi Pamela M, Pauken Kristen E, Attanasio John, Stelekati Erietta, McLane Laura M, Paley Michael A, Delgoffe Greg M, Wherry E John: Bioenergetic Insufficiencies Due to Metabolic Alterations Regulated by the Inhibitory Receptor PD-1 Are an Early Driver of CD8(+) T Cell Exhaustion. Immunity 45(2): 358-73, 08 2016.
21a Pauken Kristen E, Sammons Morgan A, Odorizzi Pamela M, Manne Sasikanth, Godec Jernej, Khan Omar, Drake Adam M, Chen Zeyu, Sen Debattama R, Kurachi Makoto, Barnitz R Anthony, Bartman Caroline, Bengsch Bertram, Huang Alexander C, Schenkel Jason M, Vahedi Golnaz, Haining W Nicholas, Berger Shelley L, Wherry E John: Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science (New York, N.Y.) 354(6316): 1160-1165, 12 2016.
304 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, D'Andrea 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, Wherry E John: T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature 545(7652): 60-65, 05 2017.
184 Kurachi Makoto, Kurachi Junko, Chen Zeyu, Johnson John, Khan Omar, Bengsch Bertram, Stelekati Erietta, Attanasio John, McLane Laura M, Tomura Michio, Ueha Satoshi, Wherry E John: Optimized retroviral transduction of mouse T cells for in vivo assessment of gene function. Nature protocols 12(9): 1980-1998, Sep 2017.
1d8 Tomov Vesselin T, Palko Olesya, Lau Chi Wai, Pattekar Ajinkya, Sun Yuhang, Tacheva Ralitza, Bengsch Bertram, Manne Sasikanth, Cosma Gabriela L, Eisenlohr Laurence C, Nice Timothy J, Virgin Herbert W, Wherry E John: Differentiation and Protective Capacity of Virus-Specific CD8+ T Cells Suggest Murine Norovirus Persistence in an Immune-Privileged Enteric Niche. Immunity 47(4): 723-738.e5, Oct 2017.
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