4.7 Article

Tumor microenvironmental signals reshape chromatin landscapes to limit the functional potential of exhausted T cells

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SCIENCE IMMUNOLOGY
卷 7, 期 74, 页码 -

出版社

AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciimmunol.abj9123

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资金

  1. NCI [F99CA222711]
  2. National Cancer Institute of the National Institutes of Health (NIH) Ruth L. Kirschstein National Research Service Award [1F30CA247034-01, T32CA082084]
  3. National Institute of General Medical Sciences of the NIH [T32GM008208]
  4. NIH New Innovator Award [DP2AI136598, R21AI135367]
  5. UPMC Hillman Cancer Center Melanoma/Skin Cancer [P50CA121973]
  6. Head and Neck Cancer SPORE [P50CA097190]
  7. Alliance for Cancer Gene Therapy
  8. Mark Foundation for Cancer Research Emerging Leader Award
  9. Cancer Research Institute Lloyd J. Old STAR Award
  10. Sy Holzer Endowed Cancer Immunotherapy Fund
  11. [T32 CA082084]
  12. [T32AI089443]
  13. [R01AI153104]
  14. [R21AI135027]
  15. [P30CA047904]

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The response rates to immunotherapy in solid tumors remain low due to the prevalence of terminally exhausted T cells. This study used CUT&RUN method to analyze the histone modification landscape of tumor-infiltrating CD8(+) T cells and found unexpected chromatin features in terminally exhausted T cells that limit their transcriptional potential. The study also linked increased histone bivalency to hypoxia exposure and showed that hypoxia-insensitive histone demethylase Kdm6b can increase cell function and promote antitumor immunity.
Response rates to immunotherapy in solid tumors remain low due in part to the elevated prevalence of terminally exhausted T cells, a hypofunctional differentiation state induced through persistent antigen and stress signaling. However, the mechanisms promoting progression to terminal exhaustion in the tumor remain undefined. Using the low-input chromatin immunoprecipitation sequencing method CUT&RUN, we profiled the histone modification landscape of tumor-infiltrating CD8(+) T cells throughout differentiation. We found that terminally exhausted T cells had unexpected chromatin features that limit their transcriptional potential. Terminally exhausted T cells had a substantial fraction of active chromatin, including active enhancers enriched for bZIP/AP-1 transcription factor motifs that lacked correlated gene expression, which was restored by immunotherapeutic costimulatory signaling. Reduced transcriptional potential was also driven by an increase in histone bivalency, which we linked directly to hypoxia exposure. Enforced expression of the hypoxia-insensitive histone demethylase Kdm6b was sufficient to overcome hypoxia, increase function, and promote antitumor immunity. Our study reveals the specific epigenetic changes mediated by histone modifications during T cell differentiation that support exhaustion in cancer, highlighting that their altered function is driven by improper costimulatory signals and environmental factors. These data suggest that even terminally exhausted T cells may remain competent for transcription in settings of increased costimulatory signaling and reduced hypoxia.

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