Engineered T cells stimulate dendritic cell recruitment and antigen spreading for potent anti-tumor immunity

Abstract

Current T cell-based immunotherapeutic strategies show limited success in treating solid tumors due to insufficient dendritic cell (DC) activity, particularly cross-presenting conventional type 1 dendritic cells (cDC1s). DC scarcity and dysfunction hinder T cell expansion and differentiation, greatly limiting anti-tumor responses. In this study, we propose a T cell engineering strategy to enhance interaction with XCR1⁺ cDC1s. Adoptively transferred T cells engineered to secrete Flt3L and XCL1 (FX) promote DC trafficking and maturation and improve DC-T cell interaction, while maintaining a pool of TCF1⁺SlamF6⁺ stem-like T cells. Importantly, FX-engineered T cells trigger robust antigen spreading and potent endogenous polyclonal T cell response, enabling the recognition and elimination of tumors with heterogeneous antigens and preventing immune escape. The therapeutic efficacy of FX-armed chimeric antigen receptor (CAR)-T cells is further validated in the Flt3KO&hFLT3LG humanized mouse model. This strategy offers a promising avenue for enhancing DC-T cell interactions, paving the way for more effective immunotherapy against solid tumors.

Keywords: CAR-T cell; antigen spreading; dendritic cell; endogenous T cell; humanized mouse model; immunotherapy; stem-like T cells.