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

• Published in: Cell reports (Cambridge) 2021-12, Vol.37 (10), p.110083-110083, Article 110083
• Main Authors: Zhao, Hanfei, Liu, Ying, Wang, Lixia, Jin, Gang, Zhao, Xiaocui, Xu, Jing, Zhang, Guangyue, Ma, Yuying, Yin, Na, Peng, Min
• Format: Article
• Language: English
• Subjects: adoptive cell transfer; Animals; cancer immunotherapy; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - transplantation; Cell Line, Tumor; Cell Proliferation; CRISPR screen; CRISPR-Cas Systems; Cytotoxicity, Immunologic; essential gene; fitness gene; Gene Expression Regulation, Neoplastic; Genome-Wide Association Study; Immunotherapy, Adoptive; Interferon Regulatory Factors - genetics; Interferon Regulatory Factors - metabolism; IRF4; Lymphocyte Activation; lymphodepletion; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neoplasms - genetics; Neoplasms - immunology; Neoplasms - metabolism; Neoplasms - therapy; Phenotype; Rc3h1; Roquin; Signal Transduction; T cell expansion; Tumor Escape; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.110083

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.