Using short hairpin RNA, Zou and Lu et al. decreased the expression of PD-1, Tim3, and Lag3 (PTL) on Her2 CAR T cells, and showed that the resulting PTL-Her2-CAR T cells exhibited enhanced control of Her2+ xenograft SKOV3 ovarian tumors in NSG mice. Mechanistically, PTL-Her2-CAR T cells had increased chromatin accessibility and upregulation of the cell adhesion molecule CD56. Homophilic interactions of CD56 molecules in trans led to increased intratumoral infiltration, IFNγ secretion, CAR T cell survival, cytotoxicity, and tumor control, ultimately prolonging mouse survival and protecting from tumor rechallenge.
The inhibitory receptors PD-1, Tim-3, and Lag-3 are highly expressed on tumor-infiltrating lymphocytes and compromise their antitumor activity. For efficient cancer immunotherapy, it is important to prevent chimeric antigen receptor T (CAR-T)-cell exhaustion. Here we downregulate these three checkpoint receptors simultaneously on CAR-T cells and that show the resulting PTL-CAR-T cells undergo epigenetic modifications and better control tumor growth. Furthermore, we unexpectedly find increased tumor infiltration by PTL-CAR-T cells and their clustering between the living and necrotic tumor tissue. Mechanistically, PTL-CAR-T cells upregulate CD56 (NCAM), which is essential for their effector function. The homophilic interaction between intercellular CD56 molecules correlates with enhanced infiltration of CAR-T cells, increased secretion of interferon-gamma, and the prolonged survival of CAR-T cells. Ectopically expressed CD56 promotes CAR-T cell survival and antitumor response. Our findings demonstrate that genetic blockade of three checkpoint inhibitory receptors and the resulting high expression of CD56 on CAR-T cells enhances the inhibition of tumor growth.
Author Info: (1) Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China. Key Laboratory of Tropical Disease Control of Ministry o
Author Info: (1) Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China. Key Laboratory of Tropical Disease Control of Ministry of Education, Guangzhou, Guangdong, 510080, China. Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Guangzhou, Guangdong, 510080, China. Qianyang Biomedical Research Institute, Guangzhou, Guangdong, 510663, China. (2) Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China. Key Laboratory of Tropical Disease Control of Ministry of Education, Guangzhou, Guangdong, 510080, China. Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Guangzhou, Guangdong, 510080, China. (3) Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China. Key Laboratory of Tropical Disease Control of Ministry of Education, Guangzhou, Guangdong, 510080, China. Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Guangzhou, Guangdong, 510080, China. (4) Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China. Key Laboratory of Tropical Disease Control of Ministry of Education, Guangzhou, Guangdong, 510080, China. Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Guangzhou, Guangdong, 510080, China. (5) Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China. Key Laboratory of Tropical Disease Control of Ministry of Education, Guangzhou, Guangdong, 510080, China. Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Guangzhou, Guangdong, 510080, China. (6) Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China. Key Laboratory of Tropical Disease Control of Ministry of Education, Guangzhou, Guangdong, 510080, China. Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Guangzhou, Guangdong, 510080, China. Qianyang Biomedical Research Institute, Guangzhou, Guangdong, 510663, China. (7) Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China. Key Laboratory of Tropical Disease Control of Ministry of Education, Guangzhou, Guangdong, 510080, China. Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Guangzhou, Guangdong, 510080, China. (8) Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China. Key Laboratory of Tropical Disease Control of Ministry of Education, Guangzhou, Guangdong, 510080, China. Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Guangzhou, Guangdong, 510080, China. (9) Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China. Key Laboratory of Tropical Disease Control of Ministry of Education, Guangzhou, Guangdong, 510080, China. Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Guangzhou, Guangdong, 510080, China. (10) Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China. Key Laboratory of Tropical Disease Control of Ministry of Education, Guangzhou, Guangdong, 510080, China. Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Guangzhou, Guangdong, 510080, China. (11) Qianyang Biomedical Research Institute, Guangzhou, Guangdong, 510663, China. (12) Qianyang Biomedical Research Institute, Guangzhou, Guangdong, 510663, China. (13) Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China. liubf5@mail.sysu.edu.cn. Key Laboratory of Tropical Disease Control of Ministry of Education, Guangzhou, Guangdong, 510080, China. liubf5@mail.sysu.edu.cn. Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Guangzhou, Guangdong, 510080, China. liubf5@mail.sysu.edu.cn. (14) Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China. zhangh92@mail.sysu.edu.cn. Key Laboratory of Tropical Disease Control of Ministry of Education, Guangzhou, Guangdong, 510080, China. zhangh92@mail.sysu.edu.cn. Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Guangzhou, Guangdong, 510080, China. zhangh92@mail.sysu.edu.cn. Qianyang Biomedical Research Institute, Guangzhou, Guangdong, 510663, China. zhangh92@mail.sysu.edu.cn.
