IL-7R licenses a population of epigenetically poised memory CD8 + T cells with superior antitumor efficacy that are critical for melanoma memory.

Autor: Micevic G; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520.; Department of Dermatology, Yale School of Medicine, New Haven, CT 06520., Daniels A; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520.; Department of Pathology, Yale School of Medicine, New Haven, CT 06520., Flem-Karlsen K; Department of Dermatology, Yale School of Medicine, New Haven, CT 06520., Park K; Department of Dermatology, Yale School of Medicine, New Haven, CT 06520., Talty R; Department of Pathology, Yale School of Medicine, New Haven, CT 06520., McGeary M; Department of Pathology, Yale School of Medicine, New Haven, CT 06520., Mirza H; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520.; Department of Pathology, Yale School of Medicine, New Haven, CT 06520., Blackburn HN; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520.; Department of Surgery, Yale School of Medicine, New Haven, CT 06520., Sefik E; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520., Cheung JF; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520., Hornick NI; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520., Aizenbud L; Yale Cancer Center, Yale School of Medicine, New Haven, CT 06520.; Department of Medicine (Medical Oncology), Yale School of Medicine, New Haven, CT 06520., Joshi NS; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520., Kluger H; Yale Cancer Center, Yale School of Medicine, New Haven, CT 06520.; Department of Medicine (Medical Oncology), Yale School of Medicine, New Haven, CT 06520.; Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520., Iwasaki A; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520.; Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520.; HHMI, Chevy Chase, MD 20815., Bosenberg MW; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520.; Department of Dermatology, Yale School of Medicine, New Haven, CT 06520.; Department of Pathology, Yale School of Medicine, New Haven, CT 06520.; Yale Cancer Center, Yale School of Medicine, New Haven, CT 06520.; Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520.; Yale Center for Immuno-Oncology, Yale School of Medicine, New Haven, CT 06520., Flavell RA; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520.; Yale Cancer Center, Yale School of Medicine, New Haven, CT 06520.; HHMI, Chevy Chase, MD 20815.
Jazyk: angličtina
Zdroj: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2023 Jul 25; Vol. 120 (30), pp. e2304319120. Date of Electronic Publication: 2023 Jul 17.
DOI: 10.1073/pnas.2304319120
Abstrakt: Recurrence of advanced melanoma after therapy is a major risk factor for reduced survival, and treatment options are limited. Antitumor immune memory plays a critical role in preventing melanoma recurrence and memory T cells could be a potent cell-based therapy, but the identity, and functional properties of the required immune cells are incompletely understood. Here, we show that an IL-7R hi tumor-specific CD8 + population is critical for antitumor memory and can be epigenetically augmented to drive powerful antitumor immune responses. Using a model of functional antimelanoma memory, we found that high IL-7R expression selectively marks a CD8 + population in lymphoid organs that plays critical roles in maintaining tumor remission after immunotherapy or surgical resection. This population has intrinsic cytotoxic activity, lacks markers of exhaustion and has superior antitumor efficacy. IL-7Rhi cells have a functionally poised epigenetic landscape regulated by DNA methylation, which can be augmented by hypomethylating agents to confer improved survival and complete melanoma clearance in naive mice. Importantly, greater than 95% of tumor-specific T cells in draining lymph nodes after therapy express high levels of IL-7R. This overlap between IL-7R hi and antigen-specific T cells allows for enrichment of a potent functional CD8 + population without determining antigen-specificity, which we demonstrate in a melanoma model without a known antigen. We identify that IL-7R expression in human melanoma is an independent prognostic factor of improved survival. These findings advance our basic understanding of antitumor memory and suggest a cell-based therapy using high IL-7R expression to enrich for a lymph node population with superior antitumor activity that can be augmented by hypomethylating agents.
Databáze: MEDLINE
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