1. Crosslinking of Ly6a metabolically reprograms CD8 T cells for cancer immunotherapy.
- Author
-
Maliah A, Santana-Magal N, Parikh S, Gordon S, Reshef K, Sade Y, Khateeb A, Richter A, Gutwillig A, Parikh R, Golan T, Krissi M, Na M, Binshtok G, Manich P, Elkoshi N, Grisaru-Tal S, Zemser-Werner V, Brenner R, Vaknine H, Nizri E, Moyal L, Amitay-Laish I, Rosemberg L, Munitz A, Kronfeld-Schor N, Shifrut E, Kobiler O, Madi A, Geiger T, Carmi Y, and Levy C
- Subjects
- Animals, Mice, Mice, Inbred C57BL, Cell Line, Tumor, Humans, Melanoma, Experimental immunology, Melanoma, Experimental therapy, Melanoma, Experimental pathology, Female, Programmed Cell Death 1 Receptor metabolism, Programmed Cell Death 1 Receptor antagonists & inhibitors, Programmed Cell Death 1 Receptor immunology, Skin Neoplasms immunology, Skin Neoplasms therapy, Skin Neoplasms pathology, Mitochondria metabolism, Melanoma immunology, Melanoma therapy, Interferon Type I metabolism, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, Antigens, Ly metabolism, Antigens, Ly immunology, Immunotherapy methods, Tumor Microenvironment immunology
- 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, Ly6ahigh 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).)- Published
- 2024
- Full Text
- View/download PDF