Antigen spreading mediates heterogeneous solid tumor eradication by DNA demethylating agent-programmed CAR T cells.

Abstract

Antigen heterogeneity substantially limits the efficacy of chimeric antigen receptor-modified T (CAR T) cell therapy against solid tumors. Our study highlights the potent antitumor activity of low-dose decitabine-primed CAR T (dCAR T) cells in solid tumor models, a benefit previously confirmed in hematologic malignancies. Notably, dCAR T cell infusion in immunocompetent mice led to substantial elimination of mixed tumor masses containing both antigen-positive and antigen-negative cells, without the need for prior lymphodepletion. Our analysis showed notable proinflammatory remodeling of the tumor immunosuppressive microenvironment. Crucially, antigen-activated dCAR T cells sustained high levels of interferon-γ production, which induced immunogenic cell death in tumor cells and activated conventional dendritic cells. This, in turn, stimulated endogenous CD8T cells, enhancing their antigen-spreading capacity and aiding in the clearance of abscopal antigen-negative tumors. These findings reveal the robust antigen-spreading capability of dCAR T cells, underscoring their clinical potential in addressing solid tumors with inherent antigen heterogeneity.