Rational design of immune gene therapy combinations via in vivo CRISPR activation screen of tumor microenvironment modulators
Rational design of immune gene therapy combinations via in vivo CRISPR activation screen of tumor microenvironment modulators
Abstract The hostile tumor microenvironment (TME) is major challenge for cancer immunotherapies. Here, we design and perform TME-targeted in vivo CRISPR activation (CRISPRa) screens to uncover factors that promote anti-tumor immunity, culminating in rationally designed immune gene therapy combinations. Through adeno-associated virus (AAV) delivery, multiplexed activation of pooled immunoregulatory genes encoding antigen presentation, cytokine, and co-stimulation molecules (APCM) leads to enhanced anti-tumor immunity. APCM screen in metastatic tumors identifies Cd80, Tnfsf14, Cxcl10, Tnfsf18, Tnfsf9, and Ifng as the top immunostimulatory candidates. AAV-mediated delivery of these factors individually or in combination shows anti-tumor efficacy across different cancer models. Further optimization pinpoints Ifng+Tnfsf9+Il12b(Il12/Il23) as a potent therapeutic combination, leading to increased IFN-γ+CD8+ and tissue-resident memory T cells. APCM therapy synergizes with CAR-T cell therapy against human solid tumors in vivo. APCM-based CRISPRa screen and gene activation systems can thus be leveraged for the rapid generation of off-the-shelf immune gene therapies against solid tumors.
Wang Guangchuan、Zhu Lvyun、Han Qin、Chow Ryan D.、He Emily、Zhang Feifei、Chen Sidi
Department 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 UniversityDepartment of Genetics, Yale University School of Medicine||System Biology Institute, Yale University||Center for Cancer Systems Biology, Yale University||Molecular Cell Biology, Genetics and Development Program, Yale University||M.D.-Ph.D. Program, Yale UniversityDepartment of Genetics, Yale University School of Medicine||System Biology Institute, Yale University||Center for Cancer Systems Biology, Yale University||Yale College, 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||Molecular Cell Biology, Genetics and Development Program, Yale University||Immunobiology Program, Yale University||Combined Program in the Biological and Biomedical Sciences, Yale University||Yale Comprehensive Cancer Center, Yale University School of Medicine||Department of Neurosurgery, Yale University School of Medicine||Yale Stem Cell Center, Yale University School of Medicine||Yale Liver Center, Yale University School of Medicine||Yale Center for Biomedical Data Science, Yale University School of Medicine
肿瘤学生物科学研究方法、生物科学研究技术
Wang Guangchuan,Zhu Lvyun,Han Qin,Chow Ryan D.,He Emily,Zhang Feifei,Chen Sidi.Rational design of immune gene therapy combinations via in vivo CRISPR activation screen of tumor microenvironment modulators[EB/OL].(2025-03-28)[2025-05-28].https://www.biorxiv.org/content/10.1101/2023.03.14.532665.点此复制
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