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

Genomic sequencing of human cancers has revealed that melanoma exhibits a strikingly high mutational density, the vast majority being recognizably derived from UV irradiation. This high mutational burden is associated with greater numbers of tumor-specific neoantigens that contribute to effective immunotherapy responses. However, the same high mutational density raises the question of how precursor melanocytes could accrue UV-induced mutations without undergoing immune recognition and destruction. In fact, immunoediting has been observed for numerous human malignancies, but surprisingly there is no evidence for such pruning in melanomas, which harbor among the highest density of mutations across cancers. Here we identify MITF, the master transcriptional regulator of melanocyte development and survival, as a lineage-specific constitutive inducer of PD-L1 expression in melanocytes. MITF directly promotes transcription of PD-L1 in melanocytes upon binding a conserved E-box-containing upstream enhancer. 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.