Rational design of immune gene therapy combinations via in vivo CRISPR activation screen of tumor microenvironment modulators
Wang, G.; Zhang, F.; Chow, R. D.; He, E.; Zhu, L.; Han, Q.; Chen, S.
Show 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-{gamma}+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.
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