Setdb1 Loss Induces Type I Interferons and Immune Clearance of Melanoma.

Despite recent advances in the treatment of melanoma, many patients with metastatic disease still succumb to their disease. To identify tumor-intrinsic modulators of immunity to melanoma, we performed a whole-genome CRISPR screen in melanoma and identified Setdb1 as well as all components of the human silencing hub complex. We found that loss of Setdb1 leads to increased immunogenicity and complete tumor clearance in a CD8+ T cell-dependent manner. Mechanistically, loss of Setdb1 causes de-repression of endogenous retroviruses (ERV) in melanoma cells and triggers tumor cell-intrinsic type I IFN signaling, upregulation of MHC-I expression, and increased CD8+ T-cell infiltration. Importantly, spontaneous immune clearance observed in Setdb1-/- tumors results in subsequent protection from other ERV-expressing tumor lines, supporting the functional antitumor role of ERV-specific CD8+ T cells found in the Setdb1-/- microenvironment. Blocking the type I IFN receptor in mice grafted with Setdb1-/- tumors decreases immunogenicity by decreasing MHC-I expression, leading to decreased T-cell infiltration and increased melanoma growth, comparable with Setdb1wt tumors. Together, these results provide key in vivo evidence of a critical role for Setdb1 and type I IFNs in generating an inflamed tumor microenvironment and potentiating tumor cell-intrinsic immunogenicity in melanoma. This study further emphasizes regulators of ERV expression and type I IFN expression as potential therapeutic targets for augmenting anticancer immune responses.