Integrated computational analysis identifies therapeutic targets with dual action in cancer cells and T cells

Many cancer drugs that target cancer cell pathways have detrimental effects on the immune system. We developed a computational platform for the identification of therapeutic targets with beneficial effects in both cancer and immune cells. ICRAFT (https://icraft.pku-genomics.org/) enables integrated analysis of immune-related CRISPR screen datasets, scRNA-Seq data, and pre-treatment RNA-Seq data from clinical trials. This platform enabled the discovery of a substantial number of targets with dual action in cancer cells and T cells. Among these, TNFAIP3, a ubiquitin-editing enzyme also known as A20, emerged as a leading target. Inactivating TNFAIP3 in cancer cells sensitizes them to immune attacks by activating the NF-?B pathway, while targeting it in T cells significantly enhances their antitumor efficacy. Overall design: To investigate the function of TNFAIP3 in the cancer cell immune response to T-cell-mediated cytotoxicity, we established A549 TNFAIP3-KO cell line by CRISPR-Cas9. To investigate the function of TNFAIP3 in CD8+ T cell immune function, we established OT-1 CD8+ T cells with Tnfaip3 knockout by CRISPR-Cas9.