Multiplexed repression of immunosuppressive genes as combinatorial cancer immunotherapy
Multiplexed repression of immunosuppressive genes as combinatorial cancer immunotherapy
Summary A complex set of pathways maintain an immunosuppressive tumor microenvironment (TME). Current cancer immunotherapies primarily rely on monoclonal antibodies targeting immune checkpoints, blocking one target at a time. Here, we devise Multiplex Universal Combinatorial Immunotherapy via Gene-silencing (MUCIG), as a versatile cancer immunotherapy approach. We harness CRISPR-Cas13d to efficiently target multiple endogenous immunosuppressive genes on demand, allowing us to silence various combinations of multiple immunosuppressive factors in the TME. Intratumoral AAV-mediated administration of MUCIG (AAV-MUCIG) elicits significant anti-tumor activity with several Cas13d gRNA compositions. A simplified off-the-shelf AAV-MUCIG with four gene combination (PGGC: Pdl1, Galectin9, Galectin3 and Cd47) has anti-tumor efficacy across different tumor types and shows abscopal effect against metastatic cancer. AAV-PGGC remodeled the TME by increasing CD8+ T cell infiltration and reducing myeloid-derived immunosuppressive cells (MDSCs). Combining AAV-PGGC with Anti-Gr1 antibody that targets MDSCs achieves synergistic effect against metastatic cancer, which reduces tumor burden and extends survival.
Chow Ryan、He Emily、Wang Guangchuan、Zhang Yueqi、Majety Medha、Zhang Feifei、Chen Sidi
Department of Genetics, Yale University School of Medicine||System Biology Institute, Yale University||Center for Cancer Systems Biology, Yale University||M.D.-Ph.D. Program, Yale University||Molecular Cell Biology, Genetics, and Development ProgramDepartment of Genetics, Yale University School of Medicine||System Biology Institute, Yale University||Center for Cancer Systems Biology, Yale University||Yale CollegeDepartment of Genetics, Yale University School of Medicine||System Biology Institute, Yale University||Center for Cancer Systems Biology, Yale UniversityDepartment of Genetics, Yale University School of Medicine||System Biology Institute, Yale University||Center for Cancer Systems Biology, Yale UniversityDepartment of Genetics, Yale University School of Medicine||System Biology Institute, Yale University||Center for Cancer Systems Biology, Yale University||Yale CollegeDepartment of Genetics, Yale University School of Medicine||System Biology Institute, Yale University||Center for Cancer Systems Biology, Yale UniversityDepartment of Genetics, Yale University School of Medicine||System Biology Institute, Yale University||Center for Cancer Systems Biology, Yale University||M.D.-Ph.D. Program, Yale University||Molecular Cell Biology, Genetics, and Development Program||Immunobiology Program, Yale University||Yale Comprehensive Cancer Center, Yale University School of Medicine||Yale Stem Cell Center, Yale University School of Medicine
肿瘤学生物科学研究方法、生物科学研究技术基础医学
Chow Ryan,He Emily,Wang Guangchuan,Zhang Yueqi,Majety Medha,Zhang Feifei,Chen Sidi.Multiplexed repression of immunosuppressive genes as combinatorial cancer immunotherapy[EB/OL].(2025-03-28)[2025-05-17].https://www.biorxiv.org/content/10.1101/2023.03.14.532668.点此复制
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