肿瘤细胞治疗研究
英文原题：In vivo genome-wide CRISPR screens identify FOXR1 as a suppressor of CD8(+) T cell antitumor immunity.
T细胞功能障碍严重限制了实体瘤中基于T细胞的免疫疗法的疗效，然而T细胞功能障碍的内在调控因子仍未完全阐明。
T细胞功能障碍严重限制了基于T细胞的免疫疗法在实体瘤中的疗效，然而T细胞功能障碍的内在调控因子仍未被完全理解。通过在肿瘤浸润CD8+ T细胞中进行体内全基因组CRISPR筛选，我们鉴定出Forkhead Box R1（FOXR1）是CD8+ T细胞效应功能的有效转录抑制因子。FOXR1的基因敲除显著增强了小鼠和人类CD8+ T细胞的细胞因子产生和细胞毒性能力，而其过表达则损害了T细胞活化和效应分子表达。在机制上，RNA-seq、CUT&Tag-seq和ATAC-seq的多组学整合揭示，FOXR1直接结合关键效应基因（包括IL2、GZMB和PRF1）的启动子区域，并抑制其表达。重要的是，在人抗CD19 CAR T细胞中敲除FOXR1提高了其对抗实体瘤的疗效，表明FOXR1是T细胞效应功能的检查点，靶向FOXR1是增强CAR T细胞对抗实体瘤疗效的有前景策略。
T cell dysfunction critically limits the efficacy of T cell-based immunotherapies in solid tumors, yet the intrinsic regulators of T cell dysfunction remain incompletely understood. Through an in vivo genome-wide CRISPR screen in tumor-infiltrating CD8 + T cells, we identified Forkhead Box R1 (FOXR1) as a potent transcriptional suppressor of CD8 + T cell effector functions. Genetic ablation of FOXR1 significantly enhanced cytokine production and cytotoxic capacity in both murine and human CD8 + T cells, whereas its overexpression impaired T cell activation and effector molecule expression. Mechanistically, multiomics integration of RNA-seq, CUT&Tag-seq, and ATAC-seq revealed that FOXR1 binds directly to promoter regions of key effector genes, including IL2, GZMB, and PRF1 , and represses their expression. Importantly, FOXR1 deletion in human anti-CD19 CAR T cells improved their efficacy against solid tumors, demonstrating that FOXR1 is a checkpoint of T cell effector function and targeting FOXR1 is a promising strategy to enhance CAR T cell efficacy against solid tumors.
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