Tumor-infiltrating M2 macrophages driven by specific genomic alterations are associated with prognosis in bladder cancer
Tumor-infiltrating M2 macrophages driven by specific genomic alterations are associated with prognosis in bladder cancer
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由特定基因组改变驱动的肿瘤浸润 M2 巨噬细胞与膀胱癌的预后相关
DOI：
10.3892/or.2019.7196
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发表时间：
2019-08-01
期刊：
影响因子：
4.2
通讯作者：
Xu, Chuanliang
中科院分区：
文献类型：
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作者：
Xue, Yongping;Tong, Liping;Xu, Chuanliang
本研究旨在探讨肿瘤微环境免疫格局影响膀胱癌的机制。CiberSort和ssGSEA分析表明，在22个肿瘤浸润性免疫细胞亚群中，M2巨噬细胞所占比例最高，并在组织学分级和病理分期较高的膀胱癌和肌肉浸润性膀胱癌(MIBC)的“基本”亚型中含量较高。Kaplan-Meier生存曲线分析表明，浸润性M2巨噬细胞数量多的患者总体和疾病特异性存活率较低。RNA测序和免疫组织化学结果表明，M2巨噬细胞富含MIBC，促进血管生成。在含有突变型TP53、Rb转录抑制因子1、磷脂酰肌醇-4，5-二磷酸3-激酶催化亚单位α、赖氨酸甲基转移酶2A、赖氨酸去甲基酶6A和载脂蛋白B mRNA编辑酶催化多肽样的膀胱癌组织中，M2巨噬细胞的浸润率较高，而在具有成纤维细胞生长因子受体3(FGFR3)、E74样ETS转录因子3、PC4和SFRS1相互作用蛋白1以及跨膜和卷曲结构域4的组织中，M2巨噬细胞的浸润率较低。此外，在FGFR3、Erb-b2受体酪氨酸激酶2、BCL2样酪氨酸激酶2、BCL2样酪氨酸激酶2扩增的组织中，M2巨噬细胞的浸润率较低端粒酶逆转录酶和tyrosine-3-monooxygenase/tryptophan-5-monooxygenase激活蛋白ZETA，以及缺失了细胞周期蛋白依赖的激酶抑制因子2A、CREB结合蛋白、AT富含相互作用结构域1A、脆性组氨酸三联体二腺苷三磷酸酶、磷酸二酯酶4D、RAD51 paralog B、核受体辅阻遏子1和蛋白酪氨酸磷酸酶D型受体。最后，7个微小(MI)RNA(miR-214-5p、miR-223-3p、miR-155-5p、miR-199A-3p、miR-199B-3p、miR-146b-5p、miR-223-5p、miR-223-3p、miR-223-3p、miR-199A-3p、miR-199B-3P、miR-146B-5P、MIR-146B-5P、MIR-146B-5P、MIR-142-5P)在至少三个突变基因中差异表达，并与M2巨噬细胞浸润呈正相关，并在高级别膀胱癌中高表达。总之，本研究得出的结论是，M2巨噬细胞是膀胱癌中主要的肿瘤浸润性免疫细胞，肿瘤特异性基因组改变导致的差异表达的miRNAs可能是M2巨噬细胞浸润的重要驱动因素。提示M2巨噬细胞的浸润可能是膀胱癌免疫治疗的潜在靶点。
The present study aimed to explore the mechanism by which the immune landscape of the tumor microenvironment influences bladder cancer. CIBERSORT and ssGSEA analyses revealed that M2 macrophages accounted for the highest proportion from 22 subsets of tumor-infiltrating immune cells and were enriched in higher histologic grade and higher pathologic stage bladder cancer and 'basal' subtype of muscle invasive bladder cancer (MIBC). Kaplan-Meier survival curve analysis indicated that patients with high numbers of infiltrating M2 macrophages had worse overall and disease-specific survival rates. RNA sequencing and immunohistochemistry results indicated that M2 macrophages were enriched in MIBC and promoted angiogenesis. M2 macrophage infiltration was higher in bladder cancer tissues with mutant TP53, RB transcriptional corepressor 1, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha, lysine methyltransferase 2A, lysine demethylase 6A and apolipoprotein B mRNA editing enzyme catalytic-polypeptide-like, but lower in tissues with mutant fibroblast growth factor receptor 3 (FGFR3), E74-like ETS transcription factor 3, PC4 and SFRS1 interacting protein 1 and transmembrane and coiled-coil domains 4. In addition, M2 macrophage infiltration was lower in the tissues with amplified FGFR3, erb-b2 receptor tyrosine kinase 2, BCL2-like 1, telomerase reverse transcriptase and tyrosine-3-monooxygenase/tryptophan-5-monooxygenase activation protein zeta, as well as in the tissues with deleted cyclin-dependent kinase inhibitor 2A, CREB binding protein, AT-rich interaction domain 1A, fragile histidine triad diadenosine triphosphatase, phosphodiesterase 4D, RAD51 paralog B, nuclear receptor corepressor 1 and protein tyrosine phosphatase receptor type D. Finally, seven micro (mi) RNAs (miR-214-5p, miR-223-3p, miR-155-5p, miR-199a-3p, miR-199b-3P, miR-146b-5p, miR-142-5p) which were expressed differentially in at least three mutant genes and were positively correlated with M2 macrophage infiltration as well as expressed highly in high grade bladder cancer were identified. Overall, the present study concluded that M2 macrophages are the predominant tumor-infiltrating immune cell in bladder cancer and differentially expressed miRNAs due to cancer-specific genomic alterations may be important drivers of M2 macrophage infiltration. These findings suggested that M2 macrophage infiltration may serve as a potential immunotherapy target in bladder cancer.