Work

1153 Melanocyte PD-L1 and type I interferons (IFN-Is) promote metastasis and immune suppression in UVB-associated melanoma

Year: 2026

Type: conference-abstract

Abstract: Background Melanoma is a highly metastatic form of skin cancer primarily caused by ultraviolet B (UVB) radiation. UVB exposure induces local and systemic IFN-I signaling, which has context-dependent roles in anti-tumor immunity. The immune checkpoint PD-L1 is frequently upregulated in melanoma, and we and others have shown tumor-intrinsic PD-L1 signals modulate IFN-I responses and promote metastasis and treatment resistance. However, how PD-L1 on melanocytes (melPD-L1), the melanoma cells of origin, regulates UVB-induced IFN-I signaling and subsequently affects melanoma development and metastasis is unreported.Methods We developed inducible, UVB-accelerable Nras-mutant melanoma mouse models in which spontaneous melanomas arise from PD-L1-replete (CTRL TNQ61R) or PD-L1-deficient (melPD-L1KO TNQ61R) melanocytes, along with derivative mT/mG reporter TNQ61R mice to track melanoma development and metastasis in situ. We used αIFNAR to block IFN-I signals and performed flow cytometry, confocal microscopy, and RNA sequencing to investigate melPD-L1 and IFN-I effects on UVB-accelerated melanoma metastasis and anti-tumor immunity.Results Clinically relevant acute UVB exposure induced sustained PD-L1 upregulation on melanocytes during early melanomagenesis. MelPD-L1 and UVB cooperatively promoted autochthonous melanoma lung metastasis and an immunosuppressive primary tumor microenvironment (TME), characterized by increased suppressive regulatory T cells and decreased cytotoxic CD8 + T cells and NK cells. UVB-exposed melPD-L1-replete tumors had elevated IFN-I signaling compared to UVB-naïve or melPD-L1KO tumors, indicating melPD-L1 amplification of UVB-induced chronic IFN-Is. Strikingly, blocking IFN-I signals prior to UVB exposure reduced UVB- and melPD-L1-dependent lung metastasis and reversed the immunosuppressive TME. In complementary transplant experiments, UVB exposure of wild-type (WT) adult mice prior to melanoma tumor challenge significantly increased primary tumor growth and lung metastasis, phenocopying the findings of our autochthonous melanoma models. Further, prior UVB exposure completely abolished the treatment efficacy of αPD-1/αCTLA-4 immune checkpoint blockade (ICB) in melanoma.Conclusions Using our novel mouse models of UVB-associated melanoma, we demonstrate that melPD-L1 amplifies UVB-induced chronic IFN-I signaling to promote long-term TME immunosuppression and distant metastasis. mT/mG TNQ61R reporter mice enabled in situ monitoring of the developing melanoma TME to show melPD-L1 upregulation during early UVB-accelerated melanomagenesis, potentially mediating downstream melPD-L1-dependent effects on metastasis and anti-melanoma immunity. Prior UVB exposure in WT adults abrogated melanoma ICB response, showing sustained consequences of UVB immune effects on ICB efficacy. Overall, these data establish novel roles of melPD-L1 and UVB-induced IFN-Is in driving melanoma development and metastasis and have important clinical implications for the treatment of NRAS-mutant melanomas, which are highly metastatic and UVB-associated.Acknowledgements NCI (R01CA292467, R01CA202965), Gmelich chair, and Guyre funds supported TJC. NIH T32AI007363 supported NS. Shared resources at Dartmouth Cancer Center are supported by NCI Cancer Center Support Grant 5P30CA023108 and NIH 1S10OD021616.Ethics Approval This study obtained all necessary ethics approvals for mouse experiments and is under the approved IACUC protocol # 2285.

Source: Journal for ImmunoTherapy of Cancer

DOI: 10.1136/jitc-2026-sitc2026.1153