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Abstract
Robust expansion of adoptively transferred Tcells is a prerequisite for effective cancer immunotherapy, but how many genes in the genome modulate Tcell expansion remains unknown. Here, we perform invivo and invitro CRISPR screens to systematically identify genes influencing CD8 Tcell expansion. In the mouse genome, ∼2,600 and ∼1,500 genes are required for optimal CD8 Tcell expansion invivo and invitro, respectively. Invivo-specific CD8 Tcell essential genes are enriched in metabolic pathways, including mitochondrial metabolism. The strongest repressor of CD8 Tcell expansion is Roquin, the ablation of which drastically boosts Tcell 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 Tcell fitness genes and suggest that targeting the Roquin-IRF4 axis is an effective strategy to enhance efficacy of adoptive transfer therapy for cancer.
Highlights
CD8 T cells play central roles in fighting against infection and cancer (Zhang and Bevan, 2011)
OT-I cells expressing Cas9 (Cas9;OT-I) were activated and infected with the retroviral single guide RNA (sgRNA) library, and cells expressing sgRNA were magnetically purified with anti-Thy1.1 nanobeads (Figure 1A)
On day 7 post-activation, cells expanded in vitro were collected, transferred T cells were isolated from spleens by flow cytometer sorting, and sgRNA distribution was analyzed by deep sequencing (Figure 1A)
Summary
CD8 T cells play central roles in fighting against infection and cancer (Zhang and Bevan, 2011). Mainly by mouse genetics, we have understood basic principles of T cell expansion and developed effective immunotherapies based on these principles, including adoptive T cell transfer therapy (ACT) of cancer (Guedan et al, 2019; Restifo et al, 2012). It remains unknown how many genes in the genome are actively involved in CD8 T cell expansion. Further dissection of the mechanisms of CD8 T cell expansion will deepen our understanding of this complex biological process and generate targets for immunotherapy
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