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

Li, Z.; Hsieh, M.-H.; Arutyunova, A.; Evans, J.; Liu, T.; Lawson, A. R. J.; Nicola, P. A.; Kildisiute, G.; Machado, H. E.; Kawam, A. A.; Wang, R.; Zeng, Q.; Jiang, N.; Wang, X.; Mannino, G.; Ren, X.; Fang, X.; Sharma, T.; Komjeti, S.; Hsiehchen, D.; Hayton, S.; Brunner, S.; Martincorena, I.; Campbell, P. J.; Zhu, H.

doi:10.1101/2025.10.13.682217

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bioRxiv · 10.1101/2025.10.13.682217

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

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Abstract

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, TYK2D810V was recurrently observed in patients with diverse cancer types. In vitro, TYK2D810V enhanced T cells effector functions and cytokine production. We generated mice with a germline Tyk2D807V mutation that recapitulated the human TYK2D810Vmutation. 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 Tyk2D807V CD8 T cells also decreased cancer growth. Thus, naturally occurring mutations in non-malignant lymphocytes can antagonize cancer and inspire new immunotherapies strategies.

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Li, Z., Hsieh, M.-H., Arutyunova, A., Evans, J., Liu, T., Lawson, A. R. J., Nicola, P. A., Kildisiute, G., Machado, H. E., Kawam, A. A., Wang, R., Zeng, Q., Jiang, N., Wang, X., Mannino, G., Ren, X., Fang, X., Sharma, T., Komjeti, S., Hsiehchen, D., Hayton, S., Brunner, S., Martincorena, I., Campbell, P. J., Zhu, H.. 2025-10-15. Somatic TYK2 activating mutations in tumor-infiltrating T cells promote anti-cancer immunity. https://doi.org/10.1101/2025.10.13.682217

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