Marietta Döring, Melanie Brux, Maciej Paszkowski-Rogacz, Pedro M Guillem-Gloria, Frank Buchholz, M Teresa Pisabarro, Mirko Theis
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引用次数: 0
摘要
肿瘤细胞通过利用抑制信号来破坏免疫监视或溶解压力。因此,人们开发了双特异性抗体,将 CTLs 引导到肿瘤部位,促进免疫依赖性细胞毒性。基于 T 细胞的免疫疗法虽然取得了成功,但并非普遍有效,部分原因是肿瘤细胞表达的促生存因子保护它们免受凋亡。在这里,我们报告了一项在人类非小细胞肺癌细胞中进行的 CRISPR/Cas9 筛选,目的是找出能使肿瘤逃避双特异性抗体作用的 CD8+ T 淋巴细胞的细胞毒性效应的基因。我们的研究表明,C22orf46基因能促进生存信号的传递,缺乏C22orf46表达的肿瘤细胞对T细胞诱导的细胞凋亡和基因毒性制剂的压力表现出更高的易感性。尽管C22orf46被注释为非编码基因,但我们证明它编码一种核极蛋白,以下简称为 "肿瘤凋亡相关蛋白1",在肺癌中上调,它与含有BH结构域的Bcl-2家族凋亡调节因子有远缘同源性。总之,这些研究结果表明 TAAP1/C22orf46 是一种促进生存的癌基因,对治疗具有重要意义。
Nucleolar protein TAAP1/C22orf46 confers pro-survival signaling in non-small cell lung cancer.
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.
期刊介绍:
Life Science Alliance is a global, open-access, editorially independent, and peer-reviewed journal launched by an alliance of EMBO Press, Rockefeller University Press, and Cold Spring Harbor Laboratory Press. Life Science Alliance is committed to rapid, fair, and transparent publication of valuable research from across all areas in the life sciences.