The CD39 positive hepatitis B virus surface protein (HBVs)-targeted CAR-T and personalized tumor-reactive CD8 + T cells exhibit potent anti-hepatocellular carcinoma (HCC) activity
Fan Zou 1 , Jizhou Tan 2 , Ting Liu 2 , Bingfeng Liu 3 , Yaping Tang 4 , Hui Zhang 5 , Jiaping Li 6
Affiliations
Affiliations
1
Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510623, China; Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China; Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology; Key Laboratory of Tropical Disease Control of Ministry of Education, Guangzhou, Guangdong, 510080, China.
2
Department of Interventional Oncology, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China.
3
Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China; Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology; Key Laboratory of Tropical Disease Control of Ministry of Education, Guangzhou, Guangdong, 510080, China.
4
Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510623, China; Department of Neurobiology, Southwest Medical University, Luzhou, Sichuan, 646000, China; Department of Imaging, Affiliated Hospital 3, Zhengzhou University, Zhengzhou 450052, China; Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
5
Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China; Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology; Key Laboratory of Tropical Disease Control of Ministry of Education, Guangzhou, Guangdong, 510080, China. Electronic address: [email protected].
6
Department of Interventional Oncology, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China. Electronic address: [email protected].
PMID: 33484968 DOI: 10.1016/j.ymthe.2021.01.021
Abstract
CD39, expressed by tumor infiltrating lymphocytes (TILs), is a marker to identify tumor-reactive T cells, which is frequently associated with stronger anti-tumor activity than bystander T cells in a variety of malignancies. Therefore, CD39 could be a promising marker for identifying the active anti-tumor immune cells used for cellular immunotherapy. To test this possibility, we constructed the hepatitis B virus surface protein (HBVs)-specific chimeric antigen receptor T-cells (HBVs-CAR-T cells) and generated the personalized tumor-reactive CD8+ T cells. We subsequently assessed their anti-tumor efficiency mainly with a co-culture system for autologous HBVs-positive HCC organoid and T cells. We found that both CD39+ HBVs-CAR-T and CD39+ personalized tumor-reactive CD8+ T cells induced much more apoptosis in HCC organoids. Although the exhaustion status of CAR-T cells increased in CD39+ CAR-T cells, triple knockdown of PD-1, Tim-3, and Lag-3 with shRNAs furtherly enhanced anti-tumor activity in CD39+ CAR-T cells. Furthermore, these CD39+ CAR-T cells exerted an increased secretion of interferon-γ and stronger anti-tumor effect in patient-derived xenograft mouse model. Our findings demonstrated that CD39 could be a promisingly biomarker to enrich active immune cells and become an indicator marker for evaluating the prognosis of immunotherapy for HCC patients.