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在一部分癌症中，转录延伸缺陷导致免疫疗法耐药性。

Defective transcription elongation in a subset of cancers confers immunotherapy resistance.

机构信息

Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, 45229, OH, USA.

University of Cincinnati Graduate Program in Systems Biology and Physiology, Cincinnati, 45267, OH, USA.

出版信息

Nat Commun. 2018 Oct 23;9(1):4410. doi: 10.1038/s41467-018-06810-0.

DOI:10.1038/s41467-018-06810-0
PMID:30353012
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6199328/
Abstract

The nature and role of global transcriptional deregulations in cancers are not fully understood. We report that a large proportion of cancers have widespread defects in mRNA transcription elongation (TE). Cancers with TE defects (TE) display spurious transcription and defective mRNA processing of genes characterized by long genomic length, poised promoters and inducible expression. Signaling pathways regulated by such genes, such as pro-inflammatory response pathways, are consistently suppressed in TE tumors. Remarkably, TE correlates with the poor response and outcome in immunotherapy, but not chemo- or targeted therapy, -treated renal cell carcinoma and metastatic melanoma patients. Forced pharmacologic or genetic induction of TE in tumor cells impairs pro-inflammatory response signaling, and imposes resistance to the innate and adaptive anti-tumor immune responses and checkpoint inhibitor therapy in vivo. Therefore, defective TE is a previously unknown mechanism of tumor immune resistance, and should be assessed in cancer patients undergoing immunotherapy.

摘要

癌症中全局转录失调的性质和作用尚未完全阐明。我们报告称，很大一部分癌症存在广泛的 mRNA 转录延伸（TE）缺陷。具有 TE 缺陷（TE）的癌症表现出基因转录的虚假和缺陷性 mRNA 加工，其特征是基因组长度长、启动子处于静止状态和诱导表达。由此类基因调控的信号通路，如促炎反应通路，在 TE 肿瘤中始终受到抑制。值得注意的是，TE 与免疫治疗、而非化疗或靶向治疗的肾细胞癌和转移性黑色素瘤患者的不良反应和预后相关。在肿瘤细胞中强制药理学或遗传学诱导 TE 会损害促炎反应信号，从而导致对体内固有和适应性抗肿瘤免疫反应以及检查点抑制剂治疗产生耐药性。因此，TE 缺陷是肿瘤免疫抵抗的一个以前未知的机制，应该在接受免疫治疗的癌症患者中进行评估。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89ce/6199328/36d2f0274127/41467_2018_6810_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89ce/6199328/b507c1828446/41467_2018_6810_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89ce/6199328/3a5cd76fb1bf/41467_2018_6810_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89ce/6199328/7d7997a9be05/41467_2018_6810_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89ce/6199328/64472f4d4340/41467_2018_6810_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89ce/6199328/6251c97d28ac/41467_2018_6810_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89ce/6199328/a6db4a12689c/41467_2018_6810_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89ce/6199328/95d9b4de75ce/41467_2018_6810_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89ce/6199328/36d2f0274127/41467_2018_6810_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89ce/6199328/b507c1828446/41467_2018_6810_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89ce/6199328/3a5cd76fb1bf/41467_2018_6810_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89ce/6199328/7d7997a9be05/41467_2018_6810_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89ce/6199328/64472f4d4340/41467_2018_6810_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89ce/6199328/6251c97d28ac/41467_2018_6810_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89ce/6199328/a6db4a12689c/41467_2018_6810_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89ce/6199328/95d9b4de75ce/41467_2018_6810_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89ce/6199328/36d2f0274127/41467_2018_6810_Fig8_HTML.jpg

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