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

Immunotherapies that directly enhance anti-tumor CD8+ T cell responses have yielded measurable but limited success, with the loss of the antigen recognized by transferred T cell posing a major challenge, highlighting the need for alternative strategies. Productive T cell anti-tumor immunity relies heavily on dendritic cells (DC), especially cross-presenting cDC1. In this study, we demonstrate a positive correlation between XCL1 expression and the stem-like phenotype of tumor-infiltrating CD8+ T cells. The adoptive transfer of Flt3L/XCL1(FX) engineered T cells efficiently stimulates DC maturation and trafficking, which enhance the interactions between DCs and T cells, helping to maintain a pool of cycling TCF1+SlamF6+ transferred T cells and trigger the priming of endogenous anti-tumor T cells responses. Furthermore, antigen spreading induced by FX engineered T cells lead to significant inhibition of solid tumors with pre-existing antigen heterogeneity. Importantly, FX-armed CAR-T cells exhibit elevated anti-tumor efficacy in both murine and humanized mouse tumor models. Altogether, our observations highlight a novel strategy to engineer T cells for improved recruitment and physical interaction with DCs within the TME, paving the way for more effective immunotherapy against solid tumors.