显性负性 TGFβ 受体 II 与截短型 TIM3 增强 CAR-T 细胞治疗在前列腺癌中的抗肿瘤疗效

The immune checkpoint molecules, Transforming growth factor beta receptor II (TGF RII) and T cell immunoglobulin and mucin domain 3 (TIM3), have been identified as contributors to T cell immune suppression in prostate cancer. The objective of this investigation was to improve the tumor killing capability of prostate-specific membrane antigen (PSMA)-chimeric antigen receptor T (CAR-T) cells by targeting TIM3 and TGF RII simultaneously.

To generate dnTGF RII-trTIM3-PSMA-CAR-T (DT-PSMA-CAR-T) cells, the surface of PSMA-CAR-T cells was overexpressed with dominant negative TGF RII (dnTGF RII) and truncated extracellular TIM3 (trTIM3). The efficacy of DT-PSMA-CAR-T cells was assessed through in vitro killing experiments and animal experiments.

The DT-PSMA-CAR-T cells demonstrated the ability to eradicate PSMA-positive prostate cancer cells, even in the presence of exogenous TGF- and/or TIM3 activating antibodies. In addition, the cells demonstrated the ability to eliminate tumor tissue in an immunodeficient mouse model transplanted with GAL9-PSMA-PC3 cells in vitro, prolonging survival without significant toxic side effects.

This study emphasizes that upregulating dnTGF RII and trTIM3 on the surface of T cells can potentially diminish the inhibitory effects of TGF RII and TIM3.