Somatic TYK2 activating mutations in tumor-infiltrating T cells promote anti-cancer immunity

Cancer cells evolve to increase fitness and evade the immune system, but it is not clear if tumor infiltrating lymphocytes (TILs) undergo selection for somatic mutations that augment anti-cancer immunity. Using single molecule whole exome sequencing in TILs, we identified somatic mutations in Tyrosine-protein kinase 2 ( TYK2 ), several of which increased TYK2 phosphorylation, JAK-STAT signaling, and interferon gamma signaling. Among these mutations, TYK2 ^D810V was recurrently observed in patients with diverse cancer types. In vitro, TYK2 ^D810V enhanced T cells effector functions and cytokine production. We generated mice with a germline Tyk2 ^D807V mutation that recapitulated the human TYK2 ^D810V mutation. These mice were healthy and did not develop autoimmune disorders. However, they possessed enhanced anti-tumor effects in the context of syngeneic and autochthonous cancer models. Adoptive therapy with Tyk2 ^D807V CD8⁺ T cells also decreased cancer growth. Thus, naturally occurring mutations in non-malignant lymphocytes can antagonize cancer and inspire new immunotherapies strategies.