CCR5 and IL-12 co-expression in CAR T cells improves antitumor efficacy by reprogramming tumor microenvironment in solid tumors
Yonggui Tian, Liubo Zhang, Yu P, Zhen Zhang, Chang Yao, Chunyi Shen, Feng Li, Chunli Wen, Yi Zhang
Abstract
Chimeric antigen receptor (CAR) T cell therapy for solid tumors faces significant challenges, including inadequate infiltration, limited proliferation, diminished effector function of CAR T cells, and an immunosuppressive tumor microenvironment (TME). In this study, we utilized The Cancer Genome Atlas database to identify key chemokines (CCL4, CCL5, and CCR5) associated with T cell infiltration across various solid tumor types. The CCL4/CCL5-CCR5 axis emerged as significantly correlated with the presence of T cells within tumors, and enhancing the expression of CCR5 in CAR T cells bolstered their migratory capacity. Furthermore, single-cell immunoprofiling of tumor tissues revealed that macrophages within the TME primarily interact with CD8 + T cells, impeding their tumor response. However, CAR T cells engineered to secrete Interleukin (IL)-12 can counteract macrophage-mediated immunosuppression and augment T cell functionality. To address these obstacles, we employed esophageal carcinoma as a model to develop mesothelin-targeted CAR T cells co-expressing CCR5 and IL-12 (CARTmeso-5-12), subsequently assessing their antitumor capabilities in vitro and in vivo. The CARTmeso-5-12 cells demonstrated enhanced tumor infiltration due to overexpression of CCR5, and IL-12 secretion further amplified CAR T cell efficacy by attenuating the suppressive influence of tumor-infiltrating macrophages, thus improving tumor eradication.