School of Medical Instrument and Food Engineering, University of Shanghai for Science and Technology, Shanghai.
Division of Health Science, Graduate School of Medicine, Osaka University, Osaka.
Eur J Histochem. 2020 Jun 19;64(s2):3122. doi: 10.4081/ejh.2020.3122.
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.
嵌合抗原受体 (CAR) T 细胞疗法在治疗实体瘤时仍然面临免疫抑制的挑战。TGF-β 是肿瘤微环境中的关键因素之一，有助于肿瘤逃避免疫系统的监视。在这里，我们尝试使用 TGF-β 受体 I 的小分子抑制剂 Galunisertib 与 CAR T 细胞联合使用，以探索 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 可显著增强 CD133-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 显著增加了 CAR T 细胞和不表达 CAR（未转染的 T 细胞）的细胞因子分泌。Galunisertib 不影响 T 细胞的增殖、靶细胞上的抗原表达和 CAR T 细胞上的 CD69。我们发现 TGF-β 在 T 细胞自身激活时分泌，Galunisertib 可以降低 CAR T 细胞中的 TGF-β 信号。我们的研究结果可为 Galunisertib 和 CAR T 细胞联合治疗实体瘤的进一步临床前和临床研究提供依据。
