Melanocyte-specific regulation of PD-L1 by MITF confers immune tolerance to UV mutagenesis

In addition to determining baseline cutaneous PD-L1 expression, MITF helps drive PD-L1 upregulation in response to UV radiation. This PD-L1 regulatory pathway is independent of interferon (IFN) signaling, in contrast to PD-L1 on melanoma cells, which is regulated primarily by IFN signaling and is associated with inflammation in the tumor microenvironment. We further observed that UV irradiation of PD-L1–/– mice produced an exaggerated inflammatory response together with vitiligo-like epidermal melanocyte destruction.

These results suggest that within normal skin, melanocytes harbor a distinct MITF-mediated mechanism driving PD-L1 production. This PD-L1 in turn may confer local immune privilege, permitting survival of UV-mutated (neoantigen-containing) melanocytes and protecting against immune destruction of melanocytes. These findings raise the possibility that similar lineage- specific mechanisms may induce immune tolerance towards other cell types subjected to mutagenic exposures and eventual carcinogenic risk.