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 gene C22orf46 facilitates pro-survival signals and that tumor cells devoid of C22orf46 expression exhibit increased susceptibility to T cell-induced apoptosis and stress by genotoxic agents. Although annotated as a non-coding gene, we demonstrate that C22orf46 encodes 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/C22orf46 as a pro-survival oncogene with implications to therapy.

中文翻译：

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核仁蛋白 TAAP1/C22orf46 在非小细胞肺癌中赋予促生存信号。

肿瘤细胞通过利用抑制信号破坏免疫监视或裂解应激。因此，双特异性抗体已被开发用于将 CTL 引导至肿瘤部位并促进免疫依赖性细胞毒性。尽管应用成功，但基于 T 细胞的免疫疗法并未普遍有效，部分原因是肿瘤细胞表达促生存因子，保护它们免于凋亡。在这里，我们报告了人类非小细胞肺癌细胞中的 CRISPR/Cas9 筛选，旨在识别赋予肿瘤逃避双特异性抗体参与的CD8 ^{+ T 淋巴细胞细胞毒性作用的能力的基因。}我们发现基因C22orf46促进促生存信号，并且缺乏C22orf46表达的肿瘤细胞表现出对 T 细胞诱导的细胞凋亡和基因毒性剂应激的敏感性增加。尽管注释为非编码基因，但我们证明C22orf46编码一种核仁蛋白，以下称为“肿瘤凋亡相关蛋白 1”，在肺癌中表达上调，与包含 Bcl-2 家族的 BH 结构域表现出远程同源性细胞凋亡调节因子。总的来说，这些发现确定 TAAP1/ C22orf46是一种促生存癌基因，对治疗具有影响。