Center for Disease Prevention Research and Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA.
Sci Rep. 2019 Jul 29;9(1):10918. doi: 10.1038/s41598-019-47382-3.
Immune checkpoint blockade therapy (ICBT) can unleash T-cell responses against cancer. However, only a small fraction of patients exhibited responses to ICBT. The role of immune checkpoints in cancer cells is not well understood. In this study, we analyzed T-cell coinhibitory/costimulatory genes across more than 1100 samples of the Cancer Cell Line Encyclopedia (CCLE). Nearly 90% of such genes were not expressed or had low expression across the CCLE cancer cell lines. Cell line screening showed the enrichment of cancer cells deprived of the expression of CD27, CEACAM1, CTLA4, LRIG1, PDCD1LG2, or TNFRSF18, suggesting their role as tumor suppressor. The metagene expression signature derived from these six genes - Immu6Metagene was associated with prolonged survival phenotypes. A common set of five oncogenic pathways were significantly inhibited in different types of tumors of the cancer patients with good survival outcome and high Immu6Metagene signature expression. These pathways were TGF-β signaling, angiogenesis, EMT, hypoxia and mitotic process. Our study showed that oncoimmunology related molecules especially the six genes of the Immu6Metagene signature may play the tumor suppressor role in certain cancers. Therefore, the ICBT targeting them should be considered in such context to improve the efficacy.
免疫检查点阻断疗法 (ICBT) 可以激发针对癌症的 T 细胞反应。然而，只有一小部分患者对 ICBT 有反应。免疫检查点在癌细胞中的作用还不是很清楚。在这项研究中，我们分析了癌症细胞系百科全书 (CCLE) 中超过 1100 个样本中的 T 细胞共抑制/共刺激基因。这些基因中几乎有 90%在 CCLE 癌症细胞系中没有表达或低表达。细胞系筛选显示，缺乏 CD27、CEACAM1、CTLA4、LRIG1、PDCD1LG2 或 TNFRSF18 表达的癌细胞富集，表明它们具有肿瘤抑制作用。从这六个基因中得出的 metagene 表达特征——Immu6Metagene 与延长的生存表型相关。在生存结局良好和 Immu6Metagene 特征表达高的癌症患者的不同类型肿瘤中，一组共同的五种致癌途径被显著抑制。这些途径是 TGF-β 信号通路、血管生成、EMT、缺氧和有丝分裂过程。我们的研究表明，oncogenomics 相关分子，特别是 Immu6Metagene 特征的六个基因，在某些癌症中可能发挥肿瘤抑制作用。因此，在这种情况下，应该考虑针对它们的 ICBT 以提高疗效。
