Laboratory of Cancer Immunology, Department of Biomedicine, University of Basel and University Hospital of Basel, Basel, Switzerland.
Laboratory of Tumor Heterogeneity, Metastasis and Resistance, Department of Biomedicine, University of Basel and University Hospital of Basel, Basel, Switzerland.
Nat Commun. 2023 Feb 2;14(1):86. doi: 10.1038/s41467-022-35583-w.
Tumor-specific T cells are frequently exhausted by chronic antigenic stimulation. We here report on a human antigen-specific ex vivo model to explore new therapeutic options for T cell immunotherapies. T cells generated with this model resemble tumor-infiltrating exhausted T cells on a phenotypic and transcriptional level. Using a targeted pooled CRISPR-Cas9 screen and individual gene knockout validation experiments, we uncover sorting nexin-9 (SNX9) as a mediator of T cell exhaustion. Upon TCR/CD28 stimulation, deletion of SNX9 in CD8 T cells decreases PLCγ1, Ca, and NFATc2-mediated T cell signaling and reduces expression of NR4A1/3 and TOX. SNX9 knockout enhances memory differentiation and IFNγ secretion of adoptively transferred T cells and results in improved anti-tumor efficacy of human chimeric antigen receptor T cells in vivo. Our findings highlight that targeting SNX9 is a strategy to prevent T cell exhaustion and enhance anti-tumor immunity.
肿瘤特异性 T 细胞经常因慢性抗原刺激而衰竭。我们在此报告了一种人类抗原特异性的体外模型，以探索 T 细胞免疫疗法的新治疗选择。使用这种模型产生的 T 细胞在表型和转录水平上类似于肿瘤浸润性耗竭 T 细胞。通过靶向性的 CRISPR-Cas9 筛选和单个基因敲除验证实验，我们发现分选连接蛋白 9（SNX9）是 T 细胞衰竭的介导物。在 TCR/CD28 刺激下，CD8 T 细胞中 SNX9 的缺失会降低 PLCγ1、Ca 和 NFATc2 介导的 T 细胞信号传导，并降低 NR4A1/3 和 TOX 的表达。SNX9 敲除增强了过继转移 T 细胞的记忆分化和 IFNγ 分泌，并导致体内人嵌合抗原受体 T 细胞的抗肿瘤疗效得到改善。我们的研究结果强调，靶向 SNX9 是防止 T 细胞衰竭和增强抗肿瘤免疫的一种策略。
