A STUB1–CHIC2 complex inhibits CD8+ T cells to restrain tumor immunity

Abstract

In vivo CRISPR screens in CD8+ T cells have previously uncovered targets for cancer immunotherapy; however, a minority of the genome has been individually annotated, suggesting that additional regulators remain to be discovered. Here we assessed 899 genes in CD8+ T cells responding to murine melanoma and identified the E3 ubiquitin ligase STUB1 as a new negative regulator of anti-tumor CD8+ T cell function. We demonstrated that Stub1 knockout CD8+ T cells effectively control tumor growth across multiple murine models. Mechanistically, STUB1 interacts with the adapter protein CHIC2 to regulate cytokine receptor expression in mouse and human CD8+ T cells. Among the regulated cytokine receptors, interleukin-27 receptor α is essential for tumor growth control mediated by Stub1/Chic2 knockout CD8+ T cells. Together, these findings establish the STUB1–CHIC2 complex as a regulator of cytokine receptor expression in CD8+ T cells and provide rationale for inhibiting this pathway to enhance CD8+ T cell-mediated anti-tumor immunity. LaFleur, Milling et al. perform an in vivo CRISPR screen of CD8+ T cells responding to tumors. They identify the E3 ubiquitin ligase STUB1 as a potent negative regulator of CD8+ T cell responses in tumors.