A TNC scFv increases the activity and persistence of CAR T cells against solid tumors
Chimeric antigen receptor (CAR)-T cell therapy has shown limited efficacy in solid tumors due to immunosuppressive events within the tumor microenvironment (TME). Tenascin-C (TNC) is an extracellular matrix (ECM) protein highly expressed in multiple solid malignancies. To improve antitumor activity, we hypothesized that enabling CAR-T cells to secrete protein targeting ECM such as TNC, would help remove the immune barrier of tumor tissues and boost CAR-T cells function. Here, we developed an armored CAR-T system consisting of single-chain variable fragment targeting TNC (TNC-scFv) linked with traditional CAR structure that greatly improve the functions of CAR-T cells against solid tumors. In vitro and xenograft models, the TNC-scFv armored CAR-T cells exhibited the enhanced antitumor activity, improved persistence and decreased exhaustion of CAR-T cells. Single-cell RNA sequencing revealed that TNC-scFv armored CAR-T cells reprogram the TME, particularly increasing the functional CD8+ T cell infiltration. Notably, these TNC-scFv armored CAR-T cells also showed potent anti-tumor efficacy with minimal systemic toxicity in humanized xenograft models. Besides, compared to IL-2-armored CAR-T cells, the TNC-scFv and IL-2 double-armored CAR-T cells displayed superior efficacy with reduced cytokine-related toxicity. Our research provide a promising broadly applicable approach to improve CAR-T cells efficacy and safety for solid tumors.