Maliah et al. showed that mice receiving chronic UVB exposure prior to s.c. or i.v. injection of melanoma cells exhibited enhanced growth of local tumors, but not metastases; reduced skin-draining LN, but not splenic CD8+ T cell antitumor activity; and resistance to anti-PD-1 treatment. UVB-induced immunosuppression was mediated by a Ly6ahi T cell subset that was shown to be upregulated by type I IFNs secreted by DCs in the inflammatory TME. Anti-Ly6a Abs signaled T cells via cMyc to prevent loss of mitochondrial metabolism and boost the T cell response to tumor cells, even in mice resistant to anti-PD-1 treatment.
Contributed by Paula Hochman
ABSTRACT: 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.
Author Info: (1) Department of Human Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. (2) Department of Pathology, Faculty of Medicine, Tel Aviv University
Author Info: (1) Department of Human Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. (2) Department of Pathology, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. (3) The Ragon Institute of Mass General, MIT and Harvard 600/625 Main Street, Cambridge, MA, USA. (4) 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. (5) Department of Pathology, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. (6) Department of Human Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. (7) Department of Pathology, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. (8) Department of Pathology, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. (9) Department of Pathology, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. (10) Department of Human Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. (11) Department of Human Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. (12) Department of Human Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. (13) Department of Pathology, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. (14) Department of Human Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. (15) Department of Human Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. (16) Department of Human Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. (17) Department of Clinical Microbiology and Immunology, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. (18) Institute of Pathology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. (19) Institute of Oncology, E. Wolfson Medical Center, Holon, Israel. (20) Institute of Pathology, E. Wolfson Medical Center, Holon, Israel. (21) Peritoneal Surface Malignancies and Melanoma Unit, Department of Surgery A, Tel-Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel. (22) Felsenstein Medical Research Center, Tel-Aviv University and the Division of Dermatology, Rabin Medical Center, Petach Tikva, Israel. (23) Felsenstein Medical Research Center, Tel-Aviv University and the Division of Dermatology, Rabin Medical Center, Petach Tikva, Israel. (24) School of Zoology, Tel Aviv University, Tel Aviv-Yafo, Israel. (25) Department of Clinical Microbiology and Immunology, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. (26) School of Zoology, Tel Aviv University, Tel Aviv-Yafo, Israel. (27) 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. (28) Department of Clinical Microbiology and Immunology, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. (29) Department of Pathology, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. (30) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. (31) Department of Pathology, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. yaroncarmi@tauex.tau.ac.il. (32) Department of Human Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. carmitlevy@tauex.tau.ac.il.
