Co-expression of a truncated TGFβ receptor II in c-Met CAR T cells enhances antitumor activity against lung adenocarcinoma.

This study investigates the therapeutic potential of c-Met-targeted CAR T cells co-expressing a truncated TGFβ receptor II (TGFBR2-N) to overcome TGFβ1-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 TGFβ 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 TGFβ1'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-γ, IL-1β, IL-6, and TNF-α in the tumor microenvironment. These findings suggest that co-expressing TGFBR2-N in c-Met CAR T cells counteracts TGFβ1-mediated immunosuppression, enhancing their therapeutic efficacy in lung adenocarcinoma and offering a promising strategy for improving CAR T cell therapy in solid tumors.