Genome-wide fitness gene identification reveals Roquin as a potent suppressor of CD8 T cell expansion and anti-tumor immunity.

Robust expansion of adoptively transferred T cells is a prerequisite for effective cancer immunotherapy, but how many genes in the genome modulate T cell expansion remains unknown. Here, we perform in vivo and in vitro CRISPR screens to systematically identify genes influencing CD8 T cell expansion. In the mouse genome, ∼2,600 and ∼1,500 genes are required for optimal CD8 T cell expansion in vivo and in vitro , respectively. In vivo -specific CD8 T cell essential genes are enriched in metabolic pathways, including mitochondrial metabolism. The strongest repressor of CD8 T cell expansion is Roquin, the ablation of which drastically boosts T cell proliferation by enhancing cell-cycle progression and upregulation of IRF4. Roquin deficiency or IRF4 overexpression potently enhances anti-tumor immunity. These data provide a functional catalog of CD8 T cell fitness genes and suggest that targeting the Roquin-IRF4 axis is an effective strategy to enhance efficacy of adoptive transfer therapy for cancer. [Display omitted] • Genome-wide identification of CD8 T cell fitness genes in vitro and in vivo • Expansion of CD8 T cells in vivo requires many more genes than in vitro expansion • Roquin is a potent repressor of CD8 T cell expansion and anti-tumor immunity • Roquin target IRF4 overexpression boosts CD8 T cell expansion and anti-tumor immunity A canonical feature of adaptive immunity is clonal expansion. Through genome-wide CRISPR screens in vitro and in vivo , Zhao et al. systematically identify genes that modulate CD8 T cell expansion and reveal a key role of the Roquin-IRF4 axis in T cell expansion and anti-tumor immunity. [ABSTRACT FROM AUTHOR]