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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE109563 | GEO | 2026/08/07

REPOSITORIES: GEO

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Project description:Dysfunctions in melanocytes can lead to pigmentation disorders, such as albinism, or contribute to the development of melanoma, the most aggressive form of skin cancer. Epidermal melanocytes typically interact with the collagen IV-rich basement membrane, but upon injury or in pathological conditions, they can encounter environments rich in collagen I or fibronectin. While alterations in ECM composition and stiffness are known to impact cell behavior, the specific roles of each of these cues for melanocyte functions remain unclear. To explore the impact of these extrinsic cues, we here exposed murine melanocytes to different ECM proteins as well as varying substrate stiffnesses. This study identified MITF, a key regulator of melanocyte differentiation and function, as an ECM- and mechanosensitive transcription factor. We further revealed that distinct ECM proteins and substrate stiffness engage a FAK/MEK/ERK/MITF signaling axis to control melanocyte functions. Exposure of melanocytes to collagen I restricted FAK and ERK activation, promoting high nuclear MITF levels associated with melanocyte proliferation and differentiation. Conversely, fibronectin elicited elevated FAK and ERK activation, leading to low nuclear MITF, correlating with a dedifferentiated and motile phenotype. Consistent with these observations, RNA sequencing revealed that COL I supports a differentiated gene expression program, whereas FN induces a neural crest-like and dedifferentiated transcriptomic signature. Importantly, inhibiting MEK or ERK activity in melanocytes cultured on fibronectin led to increased MITF nuclear localization, and enhanced melanogenesis. Additionally, we uncovered that melanocyte mechanoresponses differ depending on the specific ECM environment. Together, these findings reveal a synergistic effect of extrinsic cues on melanocyte function, with a context-dependent MITF regulation downstream of ERK, offering new perspectives for our understanding of melanocyte-related pathologies.

Project description:Mutations in the gene encoding transcription factor TFAP2A result in pigmentation anomalies in model organisms and premature hair graying in humans. However, the pleiotropic functions of TFAP2A and its redundantly-acting paralogs have made the precise contribution of TFAP2-type activity to melanocyte differentiation unclear. Defining this contribution may help to explain why TFAP2A expression is reduced in advanced-stage melanoma compared to benign nevi. To identify genes with TFAP2A-dependent expression in melanocytes, we profile zebrafish tissue and mouse melanocytes deficient in Tfap2a, and find that expression of a small subset of genes underlying pigmentation phenotypes is TFAP2A-dependent, including Dct, Mc1r, Mlph, and Pmel. We then conduct TFAP2A ChIP-seq in mouse and human melanocytes and find that a much larger subset of pigmentation genes is associated with active regulatory elements bound by TFAP2A. These elements are also frequently bound by MITF, which is considered the “master regulator” of melanocyte development. For example, the promoter of TRPM1 is bound by both TFAP2A and MITF, and we show that the activity of a minimal TRPM1 promoter is lost upon deletion of the TFAP2A binding sites. However, the expression of Trpm1 is not TFAP2A-dependent, implying that additional TFAP2 paralogs function redundantly to drive melanocyte differentiation, which is consistent with previous results from zebrafish. Paralogs Tfap2a and Tfap2b are both expressed in mouse melanocytes, and we show that mouse embryos with Wnt1-Cre-mediated deletion of Tfap2a and Tfap2b in the neural crest almost completely lack melanocytes but retain neural crest-derived sensory ganglia. These results suggest that TFAP2 paralogs, like MITF, are also necessary for induction of the melanocyte lineage. Finally, we observe a genetic interaction between tfap2a and mitfa in zebrafish, but find that artificially elevating expression of tfap2a does not increase levels of melanin in mitfa hypomorphic or loss-of-function mutants. Collectively, these results show that TFAP2 paralogs, operating alongside lineage-specific transcription factors such as MITF, directly regulate effectors of terminal differentiation in melanocytes. In addition, they suggest that TFAP2A activity, like MITF activity, has the potential to modulate the phenotype of melanoma cells.

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

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