CAR-T（CAR-T）细胞疗法在非肿瘤性疾病中的应用
Chimeric antigen receptor T (CAR-T) cell therapy in non-oncological diseases.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
敲除 SNX9 可缓解 CD8 T 细胞耗竭，从而实现有效的细胞癌症免疫治疗
英文原题：Deletion of SNX9 alleviates CD8 T cell exhaustion for effective cellular cancer immunotherapy.
查看英文原题
Deletion of SNX9 alleviates CD8 T cell exhaustion for effective cellular cancer immunotherapy.
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中文摘要
肿瘤特异性T细胞常因慢性抗原刺激而耗竭。我们在此报告一种人类抗原特异性离体模型，用于探索T细胞免疫治疗的新治疗选择。利用该模型生成的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。通过靶向混合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细胞耗竭的介导因子。在TCR/CD28刺激下，CD8 T细胞中SNX9的缺失会降低PLCγ1、Ca2+和NFATc2介导的T细胞信号传导，并减少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，并在体内提高了人类CAR-T 细胞的抗肿瘤疗效。我们的研究结果强调，靶向SNX9是预防T细胞耗竭和增强抗肿瘤免疫的一种策略。
展开英文摘要原文
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 2+ , 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.
论文信息
- 作者
- Trefny MP、Kirchhammer N、Auf der Maur P、Natoli M、Schmid D、Germann M、Fernandez Rodriguez L、Herzig P
- 第一作者单位
- Laboratory of Cancer Immunology, Department of Biomedicine, University of Basel and University Hospital of Basel, Basel, Switzerland. marcel.trefny@unibas.ch.Switzerland
- 通讯作者单位
- Laboratory of Cancer Immunology, Department of Biomedicine, University of Basel and University Hospital of Basel, Basel, Switzerland. alfred.zippelius@usb.ch.Switzerland
- 文献类型
- 非美国政府资助研究
- 期刊
- Nature communications2023 Feb 2
- 原文标识
- PubMed 36732507 · DOI 10.1038/s41467-022-35583-w
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