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美国马萨诸塞州综合医院Marcela V. Maus研究团队发现，CAR T细胞杀伤力在实体瘤中需要IFNγR途径。该研究于2022年4月13日在线发表于国际一流学术期刊《自然》。

为了以无偏见的方式系统地识别潜在的抗性途径，研究人员在胶质母细胞瘤中进行了全基因组CRISPR敲除筛选，在这种疾病中，嵌合抗原受体（CAR）T细胞的疗效有限。研究人员发现，干扰素-γ受体（IFNγR）信号通路（IFNGR1、JAK1或JAK2）的基因缺失使胶质母细胞瘤和其他实体瘤在体外和体内都对CAR T细胞的杀伤力更强。然而，这一途径的丧失并没有使白血病或淋巴瘤细胞系对CAR T细胞不敏感。

通过转录分析，研究人员确定缺乏IFNγR1的胶质母细胞瘤细胞在暴露于CAR T细胞后，细胞粘附途径的上调率较低。研究人员发现胶质母细胞瘤细胞中IFNγR1的缺失降低了CAR T细胞的整体结合时间和亲和力。鉴于CAR T细胞不需要传统的抗原呈递途径，IFNγR信号在实体瘤对CAR T细胞的易感性方面的关键作用令人惊讶。相反，在胶质母细胞瘤中，IFNγR信号是CAR T细胞充分粘附以介导生产性细胞毒性的必要条件。

这项工作表明，非实体瘤和实体瘤与CAR T细胞的相互作用是不同的，并表明加强T细胞和肿瘤细胞之间的结合相互作用可能会改善实体肿瘤的反应。

据悉，CAR疗法对血液学恶性肿瘤的治疗产生了变革性影响，但它对实体瘤的疗效有限。实体瘤可能对CAR T细胞的细胞毒性具有细胞内在的抵抗机制。

附：英文原文

Title: CAR T cell killing requires the IFNγR pathway in solid but not liquid tumours

Author: Larson, Rebecca C., Kann, Michael C., Bailey, Stefanie R., Haradhvala, Nicholas J., Llopis, Paula Montero, Bouffard, Amanda A., Scarf, Irene, Leick, Mark B., Grauwet, Korneel, Berger, Trisha R., Stewart, Kai, Anekal, Praju Vikas, Jan, Max, Joung, Julia, Schmidts, Andrea, Ouspenskaia, Tamara, Law, Travis, Regev, Aviv, Getz, Gad, Maus, Marcela V.

Issue&Volume: 2022-04-13

Abstract: Chimeric antigen receptor (CAR) therapy has had a transformative effect on the treatment of haematologic malignancies1,2,3,4,5,6, but it has shown limited efficacy against solid tumours. Solid tumours may have cell-intrinsic resistance mechanisms to CAR T cell cytotoxicity. Here, to systematically identify potential resistance pathways in an unbiased manner, we conducted a genome-wide CRISPR knockout screen in glioblastoma, a disease in which CAR T cells have had limited efficacy7,8. We found that the loss of genes in the interferon-γ receptor (IFNγR) signalling pathway (IFNGR1, JAK1 or JAK2) rendered glioblastoma and other solid tumours more resistant to killing by CAR T cells both in vitro and in vivo. However, loss of this pathway did not render leukaemia or lymphoma cell lines insensitive to CAR T cells. Using transcriptional profiling, we determined that glioblastoma cells lacking IFNγR1 had lower upregulation of cell-adhesion pathways after exposure to CAR T cells. We found that loss of IFNγR1 in glioblastoma cells reduced overall CAR T cell binding duration and avidity. The critical role of IFNγR signalling in susceptibility of solid tumours to CAR T cells is surprising, given that CAR T cells do not require traditional antigen-presentation pathways. Instead, in glioblastoma tumours, IFNγR signalling was required for sufficient adhesion of CAR T cells to mediate productive cytotoxicity. Our work demonstrates that liquid and solid tumours differ in their interactions with CAR T cells and suggests that enhancing binding interactions between T cells and tumour cells may yield improved responses in solid tumours.

DOI: 10.1038/s41586-022-04585-5

Source: https://www.nature.com/articles/s41586-022-04585-5

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