Systemic immunosuppression from ultraviolet radiation exposure inhibits cancer immunotherapy

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Abstract
Background: Ultraviolet radiation (UVR) affects local cutaneous and systemic immunity acutely. The wavelength, pattern and intensity of UVR exposure, individual skin phototype and immune state of individuals modulate the impact of UVR systemically. Local cutaneous immunity after UVR leads to immunosuppression that impacts melanoma. However, the effects of systemic UVR-induced changes on solid cancer therapy are not known. Methods: We investigated the impact of repeated UVR exposure on systemic immunity and immune checkpoint blockade (ICB) tumor responses in colorectal cancer and melanoma mouse models. Results: Animals exposed to chronic UVR exhibit decreased ICB response, which is mediated by systemic factors. Repeated UVR exposure expanded systemic lymphocyte populations and contracted total systemic myeloid cells. Specifically, UVR expanded peripheral blood CD4 + regulatory T cells (Tregs), which in turn led to greater Treg infiltration and immunosuppression in colorectal and skin cancer, and colorectal ICB-resistant tumors expressed unique pathways of ICB resistance due to systemic UVR. The response to ICB was restored with systemic pharmacological depletion of Tregs. In preliminary human data, there is an association between the molecular evidence of repeated UVR exposure in dermal fibroblasts and higher systemic Tregs. Discussion: Our data indicate that patients with melanoma and other cancers on immunotherapy should avoid repeated sun exposure.
Funding Information
  • LEO Pharma Gold Award (NA)
  • Melanoma Research Alliance (825648)
  • Rosetrees Trust (825648)
  • Manchester Biomedical Research Centre (NIHR203308)
  • ACED (C5759/A31372)
  • Cancer Research UK (C5759/A27412)
  • Cancer Research UK (R129951)
  • Wellcome Trust (110078/Z/15/Z)

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