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PRMT1 inhibition activates the interferon pathway to potentiate antitumor immunity and enhance checkpoint blockade efficacy in melanoma

ABSTRACT: Despite the immense success of immune checkpoint blockade (ICB) in cancer treatment, many tumors, including melanoma, exhibit innate or adaptive resistance. Tumor-intrinsic T-cell deficiency and T-cell dysfunction have been identified as essential factors in the emergence of ICB resistance. Here, we found that protein arginine methyl transferase 1 (PRMT1) expression was inversely correlated with the number and activity of CD8+ T cells within melanoma specimen. PRMT1 deficiency or inhibition with DCPT1061 significantly restrained refractory melanoma growth and increased intratumoral CD8+T cells in vivo. Moreover, PRMT1 deletion in melanoma cells facilitated formation of double-stranded RNA (dsRNA) derived from endogenous retroviral elements (ERVs) and stimulated an intracellular interferon response. Mechanistically, PRMT1 deficiency repressed the expression of DNA methyltransferase 1 (DNMT1) by attenuating modification of H4R3me2a and H3K27ac at enhancer regions of DNMT1, and DNMT1 downregulation consequently activated ERV transcription and the interferon signaling. Importantly, PRMT1 inhibition with DCPT1061 synergized with PD-1 blockade to suppress tumor progression and increase the proportion of CD8+T cells as well as IFNγ+CD8+T cells in vivo. Together, these results reveal an unrecognized role and mechanism of PRMT1 in regulating antitumor T-cell immunity, suggesting PRMT1 inhibition as a potent strategy to increase the efficacy of ICB.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE240258 | GEO | 2023/11/07

REPOSITORIES: GEO

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