In vivo engineering tumor cells to a universal "all-in-one" cancer vaccine with full antigen spectrum
(1) Wang W (2) Huang Y (3) Zhang J (4) Wang Y (5) Yu Z (6) Zhang F (7) Zhang H (8) Zhang R (9) Zhong R (10) Zhong H (11) Zhang L (12) Liu C (13) Shen C (14) Li Z (15) Wang M (16) Yang X
Wang et al. engineered an “all-in-one” cancer cell-derived vaccine (UniCVac) by co-expressing CIITA, NLRC5, CD80, and IL-2 in tumor cells to mimic professional APCs with both HLA-I and HLA-II antigen presentation, co-stimulation, and T cell growth signal. UniCVac cells presented antigens to both CD4+ and CD8+ T cells in vitro, driving activation and proliferation similar to APCs. UniCVac achieved potent antitumor activity in therapeutic (NSG) models, and induced polyclonal tumor-specific T cell responses, reprogrammed the immunosuppressive TIME to be immune-permissive, and enhanced tumor control in B16 and MC38 tumor models.
Contributed by Shishir Pant
(1) Wang W (2) Huang Y (3) Zhang J (4) Wang Y (5) Yu Z (6) Zhang F (7) Zhang H (8) Zhang R (9) Zhong R (10) Zhong H (11) Zhang L (12) Liu C (13) Shen C (14) Li Z (15) Wang M (16) Yang X
Wang et al. engineered an “all-in-one” cancer cell-derived vaccine (UniCVac) by co-expressing CIITA, NLRC5, CD80, and IL-2 in tumor cells to mimic professional APCs with both HLA-I and HLA-II antigen presentation, co-stimulation, and T cell growth signal. UniCVac cells presented antigens to both CD4+ and CD8+ T cells in vitro, driving activation and proliferation similar to APCs. UniCVac achieved potent antitumor activity in therapeutic (NSG) models, and induced polyclonal tumor-specific T cell responses, reprogrammed the immunosuppressive TIME to be immune-permissive, and enhanced tumor control in B16 and MC38 tumor models.
Contributed by Shishir Pant
ABSTRACT: Cancer vaccines offer a promising strategy to initiate de novo T cell responses or enhance existing ones, either functioning independently or synergizing with T cell-modulating therapeutics to reduce tumor burden. The clinical development of cancer vaccines faces challenges such as limited antigen coverage, insufficient antigen presentation, immune suppressive microenvironment, and the availability of personalized vaccines. In this study, we developed a universal "all-in-one" cancer cell-derived vaccine (UniCVac) with comprehensive antigen spectrum coverage by programming tumor cells into antigen-presenting cells (APCs) through the codelivery of CIITA, NLRC5, CD80, and IL-2. This reprogramming mimics the professional APC phenotype, providing simultaneous HLA-I and HLA-II antigen presentation, costimulation, and T cell proliferation signals. These tumor-derived UniCVac can directly activate both CD4(+) and CD8(+) T cells in vitro, independent of APCs. In addition, their costimulation and T cell growth-stimulating capabilities result in superior CD4(+) and CD8(+) T cell activation and proliferation comparable to traditional APCs, with enhanced PI3K-AKT pathways activation. Single-cell transcriptome analysis confirmed the similarity in cellular subtypes between UniCVac-activated and traditional APC-activated T cells. In mouse models, the UniCVac vaccination reprogramed the tumor microenvironment from immunosuppressive to immune-permissive, induced robust CD4(+) and CD8(+) T cell expansion in both preventive and therapeutic tumor models, and achieved complete tumor regression in vivo. Our approach provides a platform for the development of universal cancer vaccines with full antigen spectrum coverage and the ability to directly activate both CD4(+) and CD8(+) T cells, offering potential combinatorial opportunities with existing T cell-based immunotherapies against cancer.
Author Info:
(1) Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China. (2) Sheng Yushou Center of Cell B
iology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China. (3) Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China. (4) Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China. (5) Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China. (6) Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China. (7) Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China. (8) Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China. (9) Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. (10) Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. (11) Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (12) Cellular and Molecular Medicine, School of life sciences, University of Bristol, Bristol, UK. (13) Department of mathematics and statistics, Northeastern University at Qinhuangdao, Qinhuangdao, China. (14) Department of Biomedical Sciences, University College London, London, UK. (15) Department of Gynaecology and Obstetrics, Shanghai Pudong New Area People's Hospital, Shanghai, China. (16) Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China. Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Department of Gynaecology and Obstetrics, Shanghai Pudong New Area People's Hospital, Shanghai, China. Engineering Research Center of Cell & Therapeutic Antibody, MOE, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China. State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic & Developmental Sciences, Shanghai Jiao Tong University, Shanghai, China.
