Cited by 1,348Cancer Immunotherapy and BiomarkersT-cell and B-cell ImmunologyImmunotherapy and Immune Responses

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Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade

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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·2016·Science

DOI 10.1126/science.aaf2807PMC PMC5484795

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Abstract

epigenetic landscape. These data indicate that epigenetic fate inflexibility may limit current immunotherapies.

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“Interestingly, CXXC5 has been predicted to take part in the effectiveness of anti-PD-L1 treatment (38).”
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“Whilst recent data suggest that exhausted T cells have a fixed epigenetic state, 35,36 it remains unknown whether PD-1 signalling blockade of progenitor-like T cells early in their activation has lasting functional effects.”
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“One signi ﬁ cant factor contributing to this lack of response is the dysregulation of T cells in the tumor microenvironment (TME), which can be irreversible ( Pauken et al., 2016 ; Philip et al., 2017 ).”
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The role of extracellular vesicles in immune cell exhaustion and resistance to immunotherapy
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“If the tumor burden remains high and reactivated TEX fails to clear the tumor, they eventually become re-exhausted, acquiring a fixed epigenetic state that renders them resistant to reinvigoration via PD-1 blockade [95].”
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“Additionally, while dysfunctional T cells can regain effector function via ICI, they are unable to differentiate into memory T cells (111, 112).”
Background
Tumor Microenvironment Heterogeneity, Potential Therapeutic Avenues, and Emerging Therapies
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“Recent research indicates that an exhausted state of T-cells might be irreversible due to stable epigenetic changes, limiting the effect of checkpoint blockade in general [31, 32].”
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“These results demonstrate that T Dysf cells retain a largely stable, epigenetically “scarred” chromatin state after removal of chronic signals — particularly in the PD-1 hi Tim3 + cell population — closely resembling the fixed epigenetic profile of terminally TEX cells in vivo (11, 23, 44).”
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“[38] As aPD-1 therapy enhanced the recruitment of numerous tumor-reactive T cells with new clone phenotypes into the tumor, the potential resource of Tem may be the circulating system or lymphoid organ.”
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“…indicate that the exhaustion phenotype has been reversed given the stable transcriptional pro ﬁ le and epigenetic remodeling of the terminally exhausted T cell subset; the mechanisms regulating the complete reversal of T cell exhaustion are currently the focus of extensive investigation (72 – 75).”
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Authors: Pauken, K. E., Sammons, M. A., Odorizzi, P. M., Manne, S., Godec, J., Khan, O., Drake, A. M., Chen, Z., Sen, D. R., Kurachi, M., Barnitz, R. A., Bartman, C., Bengsch, B., Huang, A. C., Schenkel, J. M., Vahedi, G., Haining, W. N., Berger, S. L., & Wherry, E. J.
Affiliations: University of Pennsylvania (US)
Harvard University (US)
Dana-Farber Cancer Institute (US)
University of Minnesota (US)
Broad Institute (US)
Corresponding author: Wherry, E. John
ORCID: Pauken, Kristen E.
Sammons, Morgan A.
Odorizzi, Pamela M.
Manne, Sasikanth
Godec, Jernej
Khan, Omar
Chen, Zeyu
Sen, Debattama R.
Kurachi, Makoto
Bartman, Caroline
Bengsch, Bertram
Huang, Alexander C.
Schenkel, Jason M.
Vahedi, Golnaz
Haining, W. Nicholas
Berger, Shelley L.
Wherry, E. John
Venue: Science
Publisher: American Association for the Advancement of Science (AAAS)
Published: 2016-12-02
Volume: 354
Issue: 6316
Pages: 1160-1165
ISSN: 0036-8075 (ISSN-L)
1095-9203
DOI: 10.1126/science.aaf2807
PMC: PMC5484795
OpenAlex: W2541574334
Cited by: 1,348
References: 37
Citations by year: 2026: 162 · 2025: 128 · 2024: 122 · 2023: 160 · 2022: 145 · 2021: 166 · 2020: 162 · 2019: 129 · 2018: 106 · 2017: 66 · 2016: 2
FWCI: 54.40
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Science (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: Robertson Foundation–Cancer Research Institute Irvington Fellowship
American Cancer Society Postdoctoral Fellowship
German Research Foundation Fellowship (BE5496/1-1)
National Institutes of Health (F30DK100159, T32 2T32CA009615-26, CA78831, AI105343, AI112521, AI082630, AI115712, AI117950, AI108545)
Topics: Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords: exhausted T cells, epigenetic stability, anti-PD-1 therapy, T cell reinvigoration, T cell exhaustion
MeSH terms: Animals, Female, Immunologic Memory, Immunotherapy, Mice, Inbred C57BL, Transcription, Genetic, Interleukin-7, CD8-Positive T-Lymphocytes, Cell Lineage, Epigenesis, Genetic, Mice, Gene Regulatory Networks, B7-H1 Antigen, Cellular Reprogramming

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Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade

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