Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Cancer Immunol Res. 2024 Jan 3;12(1):107-119. doi: 10.1158/2326-6066.CIR-23-0061.
γδ T cells are a rare but potent subset of T cells with pleiotropic functions. They commonly reside within tumors but the response of γδ T cells to tyrosine kinase inhibition is unknown. To address this, we studied a genetically engineered mouse model of gastrointestinal stromal tumor (GIST) driven by oncogenic Kit signaling that responds to the Kit inhibitor imatinib. At baseline, γδ T cells were antitumoral, as blockade of either γδ T-cell receptor or IL17A increased tumor weight and decreased antitumor immunity. However, imatinib therapy further stimulated intratumoral γδ T cells, as determined by flow cytometry and single-cell RNA sequencing (scRNA-seq). Imatinib expanded a highly activated γδ T-cell subset with increased IL17A production and higher expression of immune checkpoints and cytolytic effector molecules. Consistent with the mouse model, γδ T cells produced IL17A in fresh human GIST specimens, and imatinib treatment increased γδ T-cell gene signatures, as measured by bulk tumor RNA-seq. Furthermore, tumor γδ T cells correlated with survival in patients with GIST. Our findings highlight the interplay between tumor cell oncogene signaling and antitumor immune responses and identify γδ T cells as targets for immunotherapy in GIST.
γδ T 细胞是一种具有多种功能的罕见但有效的 T 细胞亚群。它们通常存在于肿瘤中,但 γδ T 细胞对酪氨酸激酶抑制的反应尚不清楚。为了解决这个问题,我们研究了一种由致癌性 Kit 信号驱动的胃肠道间质瘤 (GIST) 的基因工程小鼠模型,该模型对 Kit 抑制剂伊马替尼有反应。在基线时,γδ T 细胞具有抗肿瘤作用,因为阻断 γδ T 细胞受体或 IL17A 会增加肿瘤重量并降低抗肿瘤免疫力。然而,伊马替尼治疗进一步刺激了肿瘤内的 γδ T 细胞,这可以通过流式细胞术和单细胞 RNA 测序 (scRNA-seq) 来确定。伊马替尼扩增了具有更高 IL17A 产生和更高免疫检查点和细胞溶解效应分子表达的高度激活的 γδ T 细胞亚群。与小鼠模型一致,γδ T 细胞在新鲜的人类 GIST 标本中产生 IL17A,并且伊马替尼治疗增加了 γδ T 细胞基因特征,这可以通过肿瘤 RNA-seq 来衡量。此外,肿瘤 γδ T 细胞与 GIST 患者的生存相关。我们的研究结果强调了肿瘤细胞癌基因信号与抗肿瘤免疫反应之间的相互作用,并确定 γδ T 细胞是 GIST 免疫治疗的靶点。
Cancer Immunol Res. 2024-1-3
Cancer Immunol Res. 2022-10-4
Clin Cancer Res. 2014-5-1
Front Med (Lausanne). 2024-12-19
Cancer Gene Ther. 2025-1
Cancer Immunol Res. 2022-10-4
Cancer Immunol Res. 2021-5
Nat Rev Immunol. 2021-4