Journal Article

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

Wen, Kang, Zhu, Yihan, Hu, Yanfeng, Li, Xuanyi, Xiao, Ruipei, Bi, Enguang, Gong, Zhengrong, Jiang, Ling, Ren, Jie, Zhou, Yang, Liu, Hongyan, Zhang, Xiaoyong, Zhao, Wenli, Sun, Yicheng, Liu, Ziying, Wang, Yicheng

2025

Overview

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. This study demonstrates that engineering CAR T cells to express CXCL13 enhances their antitumor efficacy and significantly improves responsiveness to PD‐1 immune checkpoint blockade. CXCL13 promotes T cell persistence, and resistance to early exhaustion via the AKT‐mTOR pathway. These findings suggest a promising strategy to overcome key barriers in CAR T cell therapy for solid tumors.

• Publisher: John Wiley & Sons, Inc,Wiley
• Subject: Animals / Antigens / Cancer therapies / CAR T cells / Cell Line, Tumor / Chemokine CXCL13 - genetics / Chemokine CXCL13 - immunology / Chemokine CXCL13 - metabolism / CXCL13 / Flow cytometry / Genes / Hematology / Humans / immune checkpoint blockade / Immune Checkpoint Inhibitors - pharmacology / Immunotherapy / Immunotherapy, Adoptive - methods / Lymphocytes / Mice / Neoplasms - immunology / Neoplasms - therapy / Programmed Cell Death 1 Receptor - antagonists & inhibitors / Receptors, Chimeric Antigen - immunology / Receptors, Chimeric Antigen - metabolism / Tumor Microenvironment - immunology / Tumors