全基因组适应性基因鉴定揭示 Roquin 是 CD8 T 细胞扩增和抗肿瘤免疫的有效抑制因子

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.