Yizhao Chen, Xiangling Zhu, Yu Chen, Zhaoyi Yang, Zhaolei Shen, Mengchen Chen, Chong Liu, Yuanyuan Zhou, Huihui Wang, Mengjuan Zhu, Jiaqi Qiu, Jinhua Huang, Xintong Han, Wei Wei, LI RuiLin, Wenming Hong, Jiajie Tu
Macrophages play a key role in immunity against solid tumors. However, their development and clinical applications are limited by their difficult-to-transfect nature, low proliferative capacity, and easily changing polarization states. The combination of chimeric antigen receptor (CAR) technology with macrophages to form chimeric antigen receptor macrophages (CAR-Ms) is an emerging strategy for adoptive cell therapy. In our previous study, we confirmed that anti-CD47 CAR-Ms have potential for ovarian cancer treatment. Here, we demonstrated that the introduction of IL-21 significantly increases the tumor-suppressive effect of anti-CD47 CAR-Ms against ovarian cancer. Specifically, IL-21-modified CAR-Ms with second-generation CARs targeting CD47 showed potent tumor cell-killing activity, both in vitro and in vivo, through direct and indirect pathways (direct phagocytosis and activation of cytotoxic T lymphocytes). In addition, an IL-21 modification significantly enhanced the tumor microenvironmental regulation of immunosuppression mediated by anti-CD47 CAR-Ms in vivo, thereby improving their therapeutic efficacy in a mouse model of ovarian cancer, without any obvious adverse effects. Taken together, these results suggest that anti-CD47 CAR-Ms combined with IL-21 is a promising treatment strategy for ovarian cancer.