IL-21-armored B7H3 CAR-iNKT cells exert potent antitumor effects

Yilin Liu; Yuanyuan Dang; Chuhan Zhang; Liu Liu; Wenhui Cai; Liantao Li; Lin Fang; Meng Wang; Shunzhe Xu; Gang Wang; Junnian Zheng; Huizhong Li

doi:10.1016/j.isci.2023.108597

IL-21-armored B7H3 CAR-iNKT cells exert potent antitumor effects

iScience. 2023 Nov 30;27(1):108597. doi: 10.1016/j.isci.2023.108597. eCollection 2024 Jan 19.

Authors

Yilin Liu¹, Yuanyuan Dang¹, Chuhan Zhang¹, Liu Liu¹, Wenhui Cai¹, Liantao Li^{1

2

3}, Lin Fang^{1

2

3}, Meng Wang^{1

2

3}, Shunzhe Xu¹, Gang Wang^{1

2

3}, Junnian Zheng^{2

3}, Huizhong Li^{1

2

3}

Affiliations

¹ Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China.
² Center of Clinical Oncology, the Affiliated Hospital of Xuzhou Medical University, 99 West Huaihai Road, Xuzhou, Jiangsu 221002, China.
³ Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Med-ical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China.

Abstract

CD1d-restricted invariant NKT (iNKT) cells play a critical role in tumor immunity. However, the scarcity and limited persistence restricts their development and clinical application. Here, we demonstrated that iNKT cells could be efficiently expanded using modified cytokines combination from peripheral blood mononuclear cells. Introduction of IL-21 significantly increased the frequency of CD62L-positive memory-like iNKT cells. iNKT cells armoring with B7H3-targeting second generation CAR and IL-21 showed potent tumor cell killing activity. Moreover, co-expression of IL-21 promoted the activation of Stat3 signaling and reduced the expression of exhaustion markers in CAR-iNKT cells in vitro. Most importantly, IL-21-arming significantly prolonged B7H3 CAR-iNKT cell proliferation and survival in vivo, thus improving their therapeutic efficacy in mouse renal cancer xerograph models without observed cytokine-related adverse events. In summary, these results suggest that B7H3 CAR-iNKT armored with IL-21 is a promising therapeutic strategy for cancer treatment.

Keywords: Cancer; Cell biology; Immunology.