Dominant negative TGFβ receptor II and truncated TIM3 enhance the antitumor efficacy of CAR-T-cell therapy in prostate cancer

Lei Tang; Huimin Shao; Yao Wu; Jiawei Wang; Xueyi Qian; Lianjun He; Houbao Huang; Zhenyu Xu

doi:10.1016/j.intimp.2023.110807

Dominant negative TGFβ receptor II and truncated TIM3 enhance the antitumor efficacy of CAR-T-cell therapy in prostate cancer

Int Immunopharmacol. 2023 Nov;124(Pt A):110807. doi: 10.1016/j.intimp.2023.110807. Epub 2023 Sep 9.

Authors

Lei Tang¹, Huimin Shao², Yao Wu², Jiawei Wang¹, Xueyi Qian², Lianjun He², Houbao Huang³, Zhenyu Xu⁴

Affiliations

¹ Department of Urology, the First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui, China.
² Department of Center of Precision Medicine, the First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui, China.
³ Department of Urology, the First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui, China. Electronic address: hhb@wnmc.edu.cn.
⁴ Department of Center of Precision Medicine, the First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui, China. Electronic address: xzy0342102@sina.com.

PMID: 37690238
DOI: 10.1016/j.intimp.2023.110807

Abstract

Background: The immune checkpoint molecules, Transforming growth factor beta receptor II (TGFβRII) 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 TGFβRII simultaneously.

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

Results: The DT-PSMA-CAR-T cells demonstrated the ability to eradicate PSMA-positive prostate cancer cells, even in the presence of exogenous TGF-β 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.

Conclusions: This study emphasizes that upregulating dnTGFβRII and trTIM3 on the surface of T cells can potentially diminish the inhibitory effects of TGFβRII and TIM3.

Keywords: CAR-T; Cellular immunotherapy; Immune checkpoint molecule; Prostate cancer; TGFβRII; TIM3.