Skin mutation burden drives adaptive immunity and response to immunotherapy.

Numerous studies over the past century have reported an inverse correlation between lifetime solar ultraviolet radiation (UV) exposure and all-cancer incidence and mortality. For decades, this relationship was hypothesized to reflect the action of photosynthesized vitamin D, though subsequent clinical trials have failed to demonstrate the expected anti-cancer properties. Rather than a consequence of vitamin D, I hypothesize that this inverse correlation reflects the immune stimulatory action of UV-derived skin neoantigens. Over time, such UV-mediated immune education drives immune repertoire diversification and superior adaptive immune responses to infectious disease and cancer. This hypothesis would explain the strong positive selection for light skin pigmentation following the out-of-Africa migration among humans inhabiting northerly latitude regions, and the longstanding racial disparities in cancer and infectious disease observed in North America. It suggests that the skin comprises an important reservoir of anti-cancer T cells that may be harnessed for anti-cancer therapy, and that skin mutation burden (SMB) may serve as a predictive biomarker of immunotherapy response. I propose a novel, non-invasive method for quantifying SMB as a biomarker.