c-Met CAR-T 细胞中截短型 TGFβ 受体 II 的共表达增强对肺腺癌的抗肿瘤活性

This study investigates the therapeutic potential of c-Met-targeted CAR T cells co-expressing a truncated TGF receptor II (TGFBR2-N) to overcome TGF 1-mediated immunosuppression in lung adenocarcinoma. Bioinformatics analysis using the GEPIA2 database and single-cell RNA sequencing (scRNA-seq) revealed high c-Met expression in lung adenocarcinoma and highlighted the role of TGF signaling in modulating tumor-infiltrating T cells.

A CAR construct targeting c-Met was developed to co-express TGFBR2-N via lentiviral transduction, and CAR T cell functionality was assessed through IL-2 ELISA, flow cytometry for pSMAD2/3 signaling, CD69 and PD-1 expression, as well as proliferation and cytotoxicity assays.

Immunohistochemistry and multiplex cytokine analysis demonstrated that TGFBR2-N co-expression reduced pSMAD2/3 signaling, neutralized TGF 1's suppressive effects, and enhanced CAR T cell proliferation and cytotoxicity. In vivo, TGFBR2-N co-expression promoted tumor suppression, increased CD3 + T cell infiltration, and elevated levels of IFN- , IL-1 , IL-6, and TNF- in the tumor microenvironment.

These findings suggest that co-expressing TGFBR2-N in c-Met CAR T cells counteracts TGF 1-mediated immunosuppression, enhancing their therapeutic efficacy in lung adenocarcinoma and offering a promising strategy for improving CAR T cell therapy in solid tumors.