CXCL13 Expression Promotes CAR T Cell Antitumor Activity and Potentiates Response to PD‐1 Blockade

Immune checkpoint blockade (ICB) and chimeric antigen receptor (CAR) T cell therapies have revolutionized cancer immunotherapy, offering significant benefits across various cancers. However, challenges remain, particularly in solid tumors where immunosuppressive tumor microenvironments and T cell exhaustion limit effectiveness. Combining ICB with CAR T cell therapy has shown potential but requires further optimization for effective synergy. Here, the bioinformatic analysis identified that CXCL13 expression is highly elevated in T cells from patients who respond to ICB, indicating its possible role in enhancing T cell antitumor responses. Mouse CAR T cells are engineered to overexpress CXCL13 and observed that these cells displayed reduced exhaustion, increased central memory phenotype, and improved mitochondrial function and proliferation in an AKT-mTOR dependent manner. CXCL13-overexpressing CAR T cells show significantly increased antitumor activity in vivo, particularly when combined with PD-1 inhibition, promoting the expansion and persistence of early exhausted CD8⁺ CAR T cells. CXCL13 also conferred similar in vitro phenotypic enhancements in human CAR T cells as observed in murine cells. These results indicate that CXCL13 expression improves CAR T cell function and responsiveness to ICB, offering a promising and translationally relevant strategy to optimize CAR T cell therapy for solid tumors in clinical settings.