Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade
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epigenetic landscape. These data indicate that epigenetic fate inflexibility may limit current immunotherapies.
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Whether the epigenetic landscape of tumor cells or T cell exhaustion contributes to ICI resistance is not well understood.
“However, whether the epigenetic landscape of the tumor cells or T cell exhaustion is contributing to resistance is not well understood, leaving much room for further understanding of how epigenetics can lead to nonresponse to ICIs (108, 109).”
From Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance (2021) · cites this paper as [109]
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“Exhausted PD-1þ CD8þ T cells display a distinct chromatin landscape compared with effector T cells and TEM cells (Pauken et al, 2016; Sen et al, 2016), and these epigenetically distinct T-cell states influence whether or not exhausted PD-1þ T cells can be reprogrammed to avoid terminal exhaustion…”
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“Tox, Tox2, and Nr4a2 mRNAs were up-regulated in exhausted compared with effector cells in the LCMVmodel (13), and Tox, Tox2, and all Nr4a mRNAs were up-regulated in exhausted compared with naïve CD8 T cells (12) (SI Appendix, Fig.”
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“Through efforts to better understand the stable nature of exhaustion-associated transcriptional states, it was recently discovered that the short-lived reinvigoration of T cells during PD-1 blockade therapy was associated with preservation of the chromatin landscape (Pauken et al., 2016).”
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BackgroundInfluentialTransient rest restores functionality in exhausted CAR-T cells through epigenetic remodeling
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Disturbed mitochondrial dynamics in CD8+ TILs reinforce T cell exhaustion
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BackgroundGenome-wide CRISPR Screens in Primary Human T Cells Reveal Key Regulators of Immune Function
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ResultNavigating CAR-T cells through the solid-tumour microenvironment
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“Given the reduced efficacy of ICIs after depletion of T cell subsets, antigen presentation to amplify immune responses is likely a key function of B cells.”
BackgroundInfluentialPrecursor exhausted T cells: key to successful immunotherapy?
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CD8+ T cells in the cancer-immunity cycle
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“In addition, PD-1 blockade in TEX activates transcriptional changes associated with effector T cells, but not with memory T cells.(88) Memory T cells have greater proliferative capacity and longevity than effector T cells and are associated with greater long-term potentiation of immune responses, including those direc…”
Successful and Maladaptive T Cell Aging
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BackgroundPD-1 expression on tumor-specific T cells: Friend or foe for immunotherapy?
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Androgen receptor activity in T cells limits checkpoint blockade efficacy
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“Exhausted T cells have distinct genetic and epigenetic reprogramming states that appear to be stable and not reversible (73).”
BackgroundDendritic cells as orchestrators of anticancer immunity and immunotherapy
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“It is also possible that combination therapy may be sufficient to reverse T cell exhaustion, although this is unlikely, given the kinetics of these experiments and recent evidence that epigenetic programs enforce an exhausted cell state (29, 30).”
BackgroundResultTIM-3 restrains anti-tumour immunity by regulating inflammasome activation
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“The enrichment of chromatin remodeling factors as hits in both in vitro and in vivo screens provides a complementary message to previous epigenomic profiling studies in T cell exhaustion (Pauken et al., 2016; Sen et al., 2016; Philip et al., 2017; ScottBrowne et al., 2016).”
BackgroundInfluentialThe Diverse Function of PD-1/PD-L Pathway Beyond Cancer
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“Intriguingly, in some cases, PD-1 blockade first restored virus-specific CD8 T-cell function, but CD8 T cells subsequently became exhausted again, displaying resistance to PD-1 immunotherapy (129).”
BackgroundTargeting TREM2 on tumor-associated macrophages enhances immunotherapy
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Stromal biology and therapy in pancreatic cancer: ready for clinical translation?
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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
- Venue
- Science
- Published
- 2016-12-02
- Volume
- 354
- Issue
- 6316
- Pages
- 1160-1165
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- 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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