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

T cell inhibitory mechanisms prevent autoimmune reactions, while cancer immunotherapy aims to remove these inhibitory signals, Chronic UV exposure attenuates autoimmunity through promotion of unknown immune-suppressive mechanisms. Here we showed that mice with subcutaneous melanoma were 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 analyses, we discovered that skin-specific, UV-induced suppression of T-cells killing activity is mediated by upregulation of Ly6ahigh T-cells subpopulation. Independently of the UVB effect, Ly6ahigh T cells were induced by chronic type-1 interferon in the tumor microenvironment. Treatment with an anti-Ly6a antibody enhanced the anti-tumoral cytotoxic activity of T cells and reprogrammed their mitochondrial metabolism via the Erk/cMyc axis. Remarkably, treatment with anti-Ly6a antibody significantly inhibited tumor growth in mice resistant to anti-PD1 therapy. Applying our findings in humans could lead to a new immunotherapy treatment for patients with resistance to existing treatments.