Chimeric antigen receptor (CAR) T cell therapy still faces the challenge of immunosuppression when treating solid tumors. TGF-β is one of the critical factors in the tumor microenvironment to help tumors escape surveillance by the immune system. Here we tried using the combination of a small molecule inhibitor of TGF-β receptor I, Galunisertib, and CAR T cells to explore whether Galunisertib could enhance CAR T cell function against solid tumor cells. In vitro experiments showed Galunisertib could significantly enhance the specific cytotoxicity of both CD133- and HER2-specific CAR T cells. However, Galunisertib had no direct killing effect on target cells. Galunisertib significantly increased the cytokine secretion of CAR T cells and T cells that do not express CAR (Nontransfected T cells). Galunisertib did not affect the proliferation of T cells, the antigen expression on target cells and CD69 on CAR T cells. We found that TGF-β was secreted by T cells themselves upon activation, and Galunisertib could reduce TGF-β signaling in CAR T cells. Our findings can provide the basis for further preclinical and clinical studies of the combination of Galunisertib and CAR T cells in the treatment of solid tumors.

中文翻译：

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Galunisertib可增强嵌合抗原受体修饰的T细胞功能。

嵌合抗原受体（CAR）T细胞疗法在治疗实体瘤时仍面临免疫抑制的挑战。TGF-β是肿瘤微环境中帮助肿瘤逃避免疫系统监视的关键因素之一。在这里，我们尝试使用TGF-β受体I，Galunisertib和CAR T细胞的小分子抑制剂的组合来研究Galunisertib是否可以增强CAR T细胞对实体瘤细胞的功能。体外实验表明Galunisertib可以显着增强CD133特异性和HER2特异性CAR T细胞的特异性细胞毒性。然而，Galunisertib对靶细胞没有直接杀伤作用。Galunisertib显着增加了CAR T细胞和不表达CAR的T细胞（未转染的T细胞）的细胞因子分泌。Galunisertib不会影响T细胞的增殖，抗原在靶细胞上的表达和CD69在CAR T细胞上的表达。我们发现TGF-β在激活时由T细胞自身分泌，而Galunisertib可以减少CAR T细胞中的TGF-β信号传导。我们的发现可为Galunisertib和CAR T细胞联合治疗实体瘤提供进一步的临床前和临床研究基础。