He et al. engineered an i.v.-delivered nanoparticle containing a plasmid PαCD3&LIGHT, in which a TERT promoter drives tumor-restricted αCD3 and LIGHT expression to reprogram T cell immunity in the TME of immune-cold solid tumors. LIGHT induced HEV formation, chemokine secretion, ECM remodeling, and T cell infiltration, while αCD3 established artificial immunological synapses, amplified TCR signaling, and reinvigorated exhausted T cells. PαCD3&LIGHT suppressed multiple immune-cold solid tumor mouse models and enhanced ICB and CAR T cell efficacy, without obvious systemic toxicity. A humanized construct enhanced human CAR T activity, without systemic toxicity.
Contributed by Shishir Pant
ABSTRACT: We engineer a tumor-targeted genetic plasmid vector (P(_CD3&LIGHT)) to systematically modulate T cell immunity. The tumor-specific telomerase reverse transcriptase (TERT) promoter drives simultaneous expression of tumor necrosis factor superfamily member 14 (LIGHT) and membrane-anchored anti-CD3 single-chain variable fragment (_CD3), which are important immunomodulators with closely clinical relevance. Secreted LIGHT induces high endothelial venule formation and chemokine secretion to recruit circulating lymphocytes, while remodeling extracellular matrix to facilitate immune cell penetration into tumor parenchyma. _CD3 establishes artificial immunological synapses between tumor cells and T lymphocytes. This dual mechanism synergistically establishes tertiary lymphoid structures de novo even within deep tumor regions, harboring stem cell-like CD8(+) T cells and driving sustained immunity. Concurrently, _CD3-mediated T cell redirection not only amplifies TCR signaling but also reverses exhausted T cells. The orchestrated T cell immunity significantly potentiates checkpoint inhibitor and chimeric antigen receptor (CAR)-T cell therapies in "immune-cold" tumors without obvious side effects and also remarkably enhances the outcome of human CAR-T cells, demonstrating translational potential in solid tumor immunotherapy.
Author Info: (1) School of Life Science, Beijing Institute of Technology, Beijing 100081, China. (2) State Key Laboratory of Crop Gene Resources and Breeding, Institute of Crop Sciences, Chines
Author Info: (1) School of Life Science, Beijing Institute of Technology, Beijing 100081, China. (2) State Key Laboratory of Crop Gene Resources and Breeding, Institute of Crop Sciences, Chinese Academy of Agricultural Sciences, Beijing 100081, China. (3) School of Life Science, Beijing Institute of Technology, Beijing 100081, China. (4) School of Medical Technology, Beijing Institute of Technology, Beijing 100081, China. (5) Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Radiation Oncology, Peking University Cancer Hospital and Institute, Beijing 100142, China. (6) Department of Respiratory and Digestive, Qian'an Yanshan Hospital, Tangshan 064400, China. (7) Department of Otorhinolaryngology, Qian'an Yanshan Hospital, Tangshan 064400, China. (8) State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Chemical Biology Center, Peking University, Beijing 100191, China. (9) School of Medical Technology, Beijing Institute of Technology, Beijing 100081, China. (10) School of Life Science, Beijing Institute of Technology, Beijing 100081, China. (11) State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Chemical Biology Center, Peking University, Beijing 100191, China. (12) School of Life Science, Beijing Institute of Technology, Beijing 100081, China. Electronic address: victornia@bit.edu.cn. (13) State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Chemical Biology Center, Peking University, Beijing 100191, China; Peking University Ningbo Institute of Marine Medicine, Ningbo 315832, China. Electronic address: hyanxie@bjmu.edu.cn.
