Crosslinking of Ly6a metabolically reprograms CD8 T cells for cancer immunotherapy.

Autor: Maliah A; Department of Human Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Santana-Magal N; Department of Pathology, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Parikh S; The Ragon Institute of Mass General, MIT and Harvard 600/625 Main Street, Cambridge, MA, USA., Gordon S; Department of Human Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Reshef K; Department of Pathology, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Sade Y; Department of Human Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Khateeb A; Department of Pathology, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Richter A; Department of Pathology, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Gutwillig A; Department of Pathology, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Parikh R; Department of Human Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Golan T; Department of Human Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Krissi M; Department of Human Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Na M; Department of Pathology, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Binshtok G; Department of Human Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Manich P; Department of Human Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Elkoshi N; Department of Human Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Grisaru-Tal S; Department of Clinical Microbiology and Immunology, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Zemser-Werner V; Institute of Pathology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel., Brenner R; Institute of Oncology, E. Wolfson Medical Center, Holon, Israel., Vaknine H; Institute of Pathology, E. Wolfson Medical Center, Holon, Israel., Nizri E; Peritoneal Surface Malignancies and Melanoma Unit, Department of Surgery A, Tel-Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel., Moyal L; Felsenstein Medical Research Center, Tel-Aviv University and the Division of Dermatology, Rabin Medical Center, Petach Tikva, Israel., Amitay-Laish I; Felsenstein Medical Research Center, Tel-Aviv University and the Division of Dermatology, Rabin Medical Center, Petach Tikva, Israel., Rosemberg L; School of Zoology, Tel Aviv University, Tel Aviv-Yafo, Israel., Munitz A; Department of Clinical Microbiology and Immunology, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Kronfeld-Schor N; School of Zoology, Tel Aviv University, Tel Aviv-Yafo, Israel., Shifrut E; Department of Pathology, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.; Faculty of Life Sciences, School of Neurobiology, Biochemistry and Biophysics, Tel Aviv University, Tel Aviv, Israel.; Dotan Center for Advanced Therapies, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel., Kobiler O; Department of Clinical Microbiology and Immunology, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Madi A; Department of Pathology, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Geiger T; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Carmi Y; Department of Pathology, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. yaroncarmi@tauex.tau.ac.il., Levy C; Department of Human Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. carmitlevy@tauex.tau.ac.il.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Sep 27; Vol. 15 (1), pp. 8354. Date of Electronic Publication: 2024 Sep 27.
DOI: 10.1038/s41467-024-52079-x
Abstrakt: T cell inhibitory mechanisms prevent autoimmune reactions, while cancer immunotherapy aims to remove these inhibitory signals. Chronic ultraviolet (UV) exposure attenuates autoimmunity through promotion of poorly understood immune-suppressive mechanisms. Here we show that mice with subcutaneous melanoma are not responsive to anti-PD1 immunotherapy following chronic UV irradiation, given prior to tumor injection, due to the suppression of T cell killing ability in skin-draining lymph nodes. Using mass cytometry and single-cell RNA-sequencing analyzes, we discover that skin-specific, UV-induced suppression of T-cells killing activity is mediated by upregulation of a Ly6a high T-cell subpopulation. Independently of the UV effect, Ly6a high T cells are induced by chronic type-1 interferon in the tumor microenvironment. Treatment with an anti-Ly6a antibody enhances the anti-tumoral cytotoxic activity of T cells and reprograms their mitochondrial metabolism via the Erk/cMyc axis. Treatment with an anti-Ly6a antibody inhibits tumor growth in mice resistant to anti-PD1 therapy. Applying our findings in humans could lead to an immunotherapy treatment for patients with resistance to existing treatments.
(© 2024. The Author(s).)
Databáze: MEDLINE
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