Journal Article

Crosslinking of Ly6a metabolically reprograms CD8 T cells for cancer immunotherapy

Kobiler, Oren, Rosemberg, Luiza, Munitz, Ariel, Madi, Asaf, Maliah, Avishai, Gutwillig, Amit, Binshtok, Gal, Reshef, Keren, Geiger, Tamar, Grisaru-Tal, Sharon, Amitay-Laish, Iris, Golan, Tamar, Na, Manho, Santana-Magal, Nadine, Parikh, Roma, Brenner, Ronen, Krissi, Matan, Kronfeld-Schor, Noga, Manich, Paulee, Elkoshi, Nadav, Moyal, Lilach, Vaknine, Hananya, Gordon, Sagi, Richter, Alon, Levy, Carmit, Sade, Yuval, Zemser-Werner, Valentina, Nizri, Eran, Khateeb, Aseel, Parikh, Shivang, Shifrut, Eric, Carmi, Yaron

2024

Overview

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. Chronic UV exposure has been associated with immune system suppression. Here the authors show that enhanced tumor growth and resistance to PD1 blockade in mice exposed to UV irradiation is associated with induced expression of Ly6a in CD8 + T cells and that targeting Ly6a enhances anti-tumor immune responses in models resistant to anti-PD1.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/31 / 38/91 / 59/5 / 631/250/251 / 631/67/580 / 64/60 / 692/4028/67/1059/2325 / 82/58 / 96/21 / Animals / Antibodies / Anticancer properties / Antigens, Ly - immunology / Antigens, Ly - metabolism / Autoimmunity / Cancer / Cancer immunotherapy / CD8 antigen / CD8-Positive T-Lymphocytes - immunology / CD8-Positive T-Lymphocytes - metabolism / Cell culture / Cell Line, Tumor / Crosslinking / Cytometry / Cytotoxicity / Exposure / Female / Gene sequencing / Humanities and Social Sciences / Humans / Immune system / Immunotherapy / Immunotherapy - methods / Interferon Type I - metabolism / Irradiation / Lymph nodes / Lymphatic drainage / Lymphocytes / Lymphocytes T / Melanoma / Melanoma - immunology / Melanoma - therapy / Melanoma, Experimental - immunology / Melanoma, Experimental - pathology / Melanoma, Experimental - therapy / Mice / Mice, Inbred C57BL / Mitochondria - metabolism / multidisciplinary / PD-1 protein / Programmed Cell Death 1 Receptor - antagonists & inhibitors / Programmed Cell Death 1 Receptor - immunology / Programmed Cell Death 1 Receptor - metabolism / Science / Science (multidisciplinary) / Skin Neoplasms - immunology / Skin Neoplasms - pathology / Skin Neoplasms - therapy / Tumor microenvironment / Tumor Microenvironment - immunology / Tumors / Ultraviolet radiation