Abstract A18: In vivo CRISPR screening in syngeneic tumor models to identify novel combinations for cancer immunotherapy


 Inducible T cell Co-Stimulator (ICOS, CD278) is a receptor belonging to the CD28/CTLA-4 superfamily that is predominantly expressed on T cells following T cell receptor (TCR) activation and plays an important role in regulating adaptive immune response. ICOS represents possible node of therapeutic intervention for cancer, and as such, is under clinical evaluation. Although ICOS agonists have been shown to promote significant monotherapeutic efficacy in non-clinical studies, most patients do not respond to the single-agent approaches. Therefore, it is crucial to better understand the potential mechanisms of action as well as to develop novel combination strategies and biomarkers to best position therapeutic in the clinic. In an effort to identify novel combination partners and/or biomarkers for ICOS agonist, we utilized pooled in vivo genetic screening via CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 genome editing in the syngeneic CT26 colorectal mouse tumor model alongside agonist treatment for the target. We evaluated 509 druggable genes with four sgRNAs targeting each gene to identify genes where loss in CT26 tumor cells can increase sensitivity or resistance to this treatment. With a false discovery rate (FDR) <0.05, we were able to identify 38 sensitizing hits for ICOS agonist. To our knowledge, this is the first in vivo genetic screening in mouse models aiming to uncover potential combinational targets for anti-ICOS agonist. Importantly, this screening strategy can be adapted to orthogonal tumor types to confirm current hits or identify undescribed combination targets for a range of other immunotherapeutic approaches.
 Citation Format: Qila Sa, Hongyu Liang, Rumen Kostadinov, Jong Yu, Jeremy Waight, Stephanie Van Horn, Qing Xie, Sue Griffin, Chris Hopson, Ning Sun. In vivo CRISPR screening in syngeneic tumor models to identify novel combinations for cancer immunotherapy [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A18.