Nucleolar protein TAAP1/C22orf46confers pro-survival signaling in non-small cell lung cancer

Abstract

Tumor cells subvert immune surveillance or lytic stress by harnessing inhibitory signals. Hence, bispecific antibodies have been developed to direct CTLs to the tumor site and foster immune-dependent cytotoxicity. Although applied with success, T cell–based immunotherapies are not universally effective partially because of the expression of pro-survival factors by tumor cells protecting them from apoptosis. Here, we report a CRISPR/Cas9 screen in human non-small cell lung cancer cells designed to identify genes that confer tumors with the ability to evade the cytotoxic effects of CD8+T lymphocytes engaged by bispecific antibodies. We show that the geneC22orf46facilitates pro-survival signals and that tumor cells devoid ofC22orf46expression exhibit increased susceptibility to T cell–induced apoptosis and stress by genotoxic agents. Although annotated as a non-coding gene, we demonstrate thatC22orf46encodes a nucleolar protein, hereafter referred to as “Tumor Apoptosis Associated Protein 1,” up-regulated in lung cancer, which displays remote homologies to the BH domain containing Bcl-2 family of apoptosis regulators. Collectively, the findings establish TAAP1/C22orf46as a pro-survival oncogene with implications to therapy.