Crosslinking of Ly6a metabolically reprograms CD8 T cells for cancer immunotherapy
Avishai Maliah, Nadine Santana-Magal, Shivang Parikh, Sagi Gordon, Keren Reshef, Yuval Sade, Aseel Khateeb, A. Richter, Amit Gutwillig, Roma Parikh, Tamar Golan, Matan Krissi, Manho Na, Gal Binshtok, Paulee Manich, Nadav Elkoshi, Sharon Grisaru‐Tal, Valentina Zemser‐Werner, Ronen Brenner, Hananya Vaknine, Eran Nizri, Lilach Moyal, Iris Amitay‐Laish, Luiza Rosemberg, Ariel Munitz, Noga Kronfeld‐Schor, Eric Shifrut, Oren Kobiler, Asaf Madi, Tamar Geiger, Yaron Carmi, Carmit Levy
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 Ly6ahigh 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. 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.