Targeting CD276 by CAR-T cells induces regression of esophagus squamous cell carcinoma in xenograft mouse models

Yujing Xuan; Yuqiao Sheng; Daiqun Zhang; Kai Zhang; Zhen Zhang; Yu Ping; Shumin Wang; Xiaojuan Shi; Jingyao Lian; Kangdong Liu; Yi Zhang; Feng Li

doi:10.1016/j.tranon.2021.101138

Targeting CD276 by CAR-T cells induces regression of esophagus squamous cell carcinoma in xenograft mouse models

Transl Oncol. 2021 Aug;14(8):101138. doi: 10.1016/j.tranon.2021.101138. Epub 2021 May 27.

Authors

Yujing Xuan¹, Yuqiao Sheng², Daiqun Zhang¹, Kai Zhang¹, Zhen Zhang¹, Yu Ping¹, Shumin Wang¹, Xiaojuan Shi¹, Jingyao Lian¹, Kangdong Liu³, Yi Zhang⁴, Feng Li⁵

Affiliations

¹ Biotherapy Center, Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; Henan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou, Henan, China; State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, Henan, China.
² Medical Research Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
³ Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China; State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, Henan, China; China-US Hormel (Henan) Cancer Institute, Zhengzhou, Henan, China. Electronic address: kdliu@zzu.edu.cn.
⁴ Biotherapy Center, Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; Henan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou, Henan, China; School of Life Sciences, Zhengzhou University, Zhengzhou, Henan, China; State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, Henan, China. Electronic address: yizhang@zzu.edu.cn.
⁵ Biotherapy Center, Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; Henan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou, Henan, China; State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, Henan, China. Electronic address: lifeng01@msn.com.

Abstract

Esophageal cancer, including esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC), has a poor prognosis and limited therapeutic options. Chimeric antigen receptor (CAR)-T cells represent a potential ESCC treatment. In this study, we examined CD276 expression in healthy and esophageal tumor tissues and explored the tumoricidal potential of CD276-targeting CAR-T cells in ESCC. CD276 was strongly and homogenously expressed in ESCC and EAC tumor lesions but mildly in healthy tissues, representing a good target for CAR-T cell therapy. We generated CD276-directed CAR-T cells with a humanized antigen-recognizing domain and CD28 or 4-1BB co-stimulation. CD276-specific CAR-T cells efficiently killed ESCC tumor cells in an antigen-dependent manner both in vitro and in vivo. In patient-derived xenograft models, CAR-T cells induced tumor regression and extended mouse survival. In addition, CAR-T cells generated from patient T cells demonstrated potent cytotoxicity against autologous tumor cells. Our study indicates that CD276 is an attractive target for ESCC therapy, and CD276-targeting CAR-T cells are worth testing in ESCC clinical trials.

Keywords: CAR-T cell; CD276; Co-stimulation; Esophageal cancer; Patient-derived xenograft.