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1025 Tumor-specific CD8+ T cells epigenetically licensed by IL-7R are critical for anti-tumor immunity in melanoma
  1. Goran Micevic1,
  2. Andrew Daniels1,
  3. Karine Flem-Karlsen1,
  4. Koonam Park1,
  5. Ronan Talty1,
  6. Meaghan McGeary1,
  7. Haris Mirza1,
  8. Holly N Blackburn1,
  9. Esen Sefik1,
  10. Julie F Cheung1,
  11. Noah Hornick2,
  12. Lilach Aizenbud1,
  13. Nikhil Joshi1,
  14. Harriet Kluger1,
  15. Akiko Iwasaki1,
  16. Marcus Bosenberg1 and
  17. Richard Flavell1
  1. 1Yale University, New Haven, CT, USA
  2. 2Oregon Health and Science University, Portland, OR, USA
  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.


Background Recurrence of advanced melanoma after checkpoint therapy is a major risk factor for death, and treatment options are limited. Anti-tumor memory plays a critical role in preventing recurrence, but the identity, location and functional properties of the immune cells required for anti-tumor memory are not understood.

Methods Using a mouse model that allows tracking tumor-specific CD8+ T cells, immunophenotyping using flow cytometry and single cell analyses with RNA-Seq, CITE-Seq and ATAC-Seq, we isolated and characterized T-cell populations in lymphoid organs after immunotherapy and tested their functional roles in maintaining tumor remission in mice in vivo. We investigated our findings in large human melanoma cohorts at Yale and from other institutions.

Results Here, we show that an IL-7Rhi tumor-specific CD8+ population with a distinct epigenetic landscape is critical for antitumor memory and can be epigenetically augmented to drive powerful anti-tumor immune responses.This IL-7Rhi memory CD8+ population expresses intrinsic cytotoxic activity, potently upregulates effector genes and cytokines in response to tumor re-challenge and lacks exhaustion markers. The rapid cytotoxic response is enabled by a functionally poised epigenetic landscape, which can be augmented by hypomethylating agents ex vivo. The IL-7Rhi population has superior antitumor efficacy and adoptive transfer confers improved survival and melanoma clearance in 80% of mice. Importantly, greater than 95% of tumor-specific T-cells in lymph nodes after immunotherapy express high levels of IL-7R. This overlap between IL-7Rhi and tumor-specificity allows for enrichment of a potent functional T cell subset without determining neoantigens, which we demonstrate in a melanoma model without a known antigen.Integrating our findings with human melanoma, we identify that IL-7R expression in the TME is an independent prognostic factor of improved survival.

Conclusions These findings advance our understanding of anti-tumor memory and suggest a novel T cell-based therapy for melanoma using high IL-7R expression to enrich for a population with superior anti-tumor activity that can be augmented by hypomethylating agents.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See

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