Zhang and Zhong et al. focused on the role of glycosaminoglycans (GAGs) in regulating T cell responses in the TME. In multiple tumor models (pancreatic, breast, lung), a CD20-targeted CAR expressing full length OX40 showed superior antitumor efficacy in an OX40L-dependent and independent manner, suggesting an unidentified OX40L. Whole genome screening revealed that heparan sulfate (HS) and heparin directly bound to and activated OX40, and like OX40L, activated AKT, MAPK, and NFκB signaling. Functionally, the HS–OX40 interaction enhanced cell adhesion and avidity of CAR T cell binding to tumor cells, and increased solid tumor cell penetration.
Contributed by Katherine Turner
ABSTRACT: Although chimeric antigen receptor (CAR)-modified T cells have shown great success in treating B cell malignancies, they have demonstrated only limited efficacy against solid tumors. Here, we designed a CAR by integrating an antigen-independent OX40 that showed superior antitumor efficacy against multiple solid tumors. We unexpectedly found, through a CRISPR-Cas9-based whole-genome screen, that heparan sulfate is a ligand for OX40. We found that heparan sulfate can directly bind OX40 at the biochemical and cellular levels and that the interaction of heparan sulfate and OX40 activated the AKT, MAPK, and NF-_B signaling pathways. Functionally, the heparan sulfate-OX40 interaction enhanced cell adhesion and CAR T cell functional binding avidity to tumor cells. In vivo, OX40-expressing CAR T cells exhibited increased solid tumor infiltration and persistence dependent on the OX40-heparan sulfate interaction. Our findings provide insights into a glycan-costimulation interaction that is capable of regulating T cell immunity and has potential application in CAR T cell optimization.
Author Info: (1) Shanghai Lung Cancer Center, Shanghai Key Laboratory of Thoracic Tumor Biotherapy, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, C
Author Info: (1) Shanghai Lung Cancer Center, Shanghai Key Laboratory of Thoracic Tumor Biotherapy, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China. Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China. (2) Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China. (3) Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China. (4) Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China. (5) Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China. (6) Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China. (7) Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China. (8) Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China. (9) Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China. (10) Shanghai Lung Cancer Center, Shanghai Key Laboratory of Thoracic Tumor Biotherapy, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China. (11) Department of Immunology, School of BioMedicine, Mongolian National University of Medical Sciences, Ulaanbaatar 14210, Mongolia. (12) Department of Immunology, School of BioMedicine, Mongolian National University of Medical Sciences, Ulaanbaatar 14210, Mongolia. Central Clinical Laboratory, Mongolia Japan Hospital, Mongolian National University of Medical Sciences, Ulaanbaatar 14210, Mongolia. (13) Department of Immunology, School of BioMedicine, Mongolian National University of Medical Sciences, Ulaanbaatar 14210, Mongolia. (14) Department of Immunology, School of BioMedicine, Mongolian National University of Medical Sciences, Ulaanbaatar 14210, Mongolia. (15) Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China. Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China. Joint International Research Laboratory of Metabolic and Developmental Sciences, Shanghai Jiao Tong University, Shanghai 200240, China. Department of Gynaecology and Obstetrics, Shanghai Pudong New Area People's Hospital, Shanghai 200240, China. Engineering Research Center of Cell and Therapeutic Antibody, MOE, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China.
