Reconstruction of Immune Microenvironment and Signaling Pathways in Endometrioid Endometrial Adenocarcinoma During Formation of Lymphovascular Space Involvement and Lymph Node Metastasis.
Reconstruction of Immune Microenvironment and Signaling Pathways in Endometrioid Endometrial Adenocarcinoma During Formation of Lymphovascular Space Involvement and Lymph Node Metastasis.
复制标题
子宫内膜样腺癌淋巴管间隙受累及淋巴结转移过程中免疫微环境及信号通路的重建
DOI：
10.3389/fonc.2020.595082
复制
发表时间：
2020
影响因子：
4.7
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Cheng Y;Zhang X;Wang Z;Wang J
背景癌基因的扩增或突变以及逃避免疫监视系统促进肿瘤转移。然而，在子宫内膜样腺癌（EEA）淋巴血管间隙受累（LVSI）和淋巴结（LN）转移的形成过程中，免疫微环境和信号通路的微妙变化知之甚少。患者与方法我们使用Nanostring PanCancer IO 360 Panel检测了24例EEAs和良性妇科疾病石蜡包埋组织中750个癌基因和与肿瘤微环境和免疫反应相关的基因的mRNA水平，检测了肿瘤免疫相关信号通路和免疫细胞亚型。内参基因用于数据标准化。结果在EEA进展过程中，LVSI形成过程中血管生成和免疫细胞粘附信号通路被激活。然而，在LVSI向LN转移的发展过程中，免疫系统信号通路被显著抑制，包括抗原呈递、细胞毒性、淋巴区室、干扰素信号通路和共刺激信号通路。与EEA合并LVSI组相比，EEA合并LN转移组中免疫相关基因（CD 69、HLA-DOA、ATF 3、GBP 1、AP 2、DTX 3L、EGR 1、GBP 4、TAP 1、EIF 2AK 2、MX 1、ISG 15、STAT 1和HLA-AK）表达明显下调。相反，缺氧，代谢应激，表观遗传调控，基质重塑，转移信号通路不断激活LN转移。我们还发现中性粒细胞、巨噬细胞和肥大细胞可能参与了EEA中LVSI的形成和LN转移。结论EEA对淋巴结转移有明显的免疫抑制作用。一些癌基因，基质重塑和缺氧相关基因，和中性粒细胞的签名表现出较高的表达，这表明它们作为治疗靶点的潜力，并提供新的免疫治疗策略，在EEA在LN转移。
Background The amplification or mutation of oncogenes and escape from immune surveillance systems promote tumor metastasis. However, subtle changes in the immune microenvironment and signaling pathways are poorly understood during the formation of lymphovascular space involvement (LVSI) and lymph node (LN) metastasis of endometrioid endometrial adenocarcinoma (EEA). Patients and methods We detected tumor immunology-related signaling pathways and immunocyte subtypes according to the mRNA levels of 750 oncogenes and genes relating to the tumor microenvironment and immune response using the Nanostring PanCancer IO 360 Panel in 24 paraffin-embedded tissues of EEAs and benign gynecological diseases. Internal reference genes were used for data normalization. Results Angiogenesis and immune cell adhesion signaling pathways were activated during LVSI formation of EEA progression. However, during the development of LVSI to LN metastasis, immune system signaling pathways were significantly inhibited, including antigen presentation, cytotoxicity, lymphoid compartment, interferon signaling, and costimulatory signaling pathways. Immune-related genes (CD69, HLA-DOA, ATF3, GBP1, AP2, DTX3L, EGR1, GBP4, TAP1, EIF2AK2, MX1, ISG15, STAT1, and HLA-DRA) were significantly downregulated in EEA with LN metastasis compared to those in EEA with LVSI. Instead, hypoxia, metabolic stress, epigenetic regulation, matrix remodeling, and metastasis signaling pathways were continuously activated in LN metastasis. We also found that neutrophils, macrophages, and mast cells might be involved in LVSI formation and LN metastasis in EEA. Conclusions EEA with metastatic LNs showed significant immunosuppressive effects. Some oncogenes, matrix remodeling- and hypoxia-related genes, and neutrophil signatures showed higher expression, suggesting their potential as therapeutic targets and offering new immunotherapy strategies in EEA during LN metastasis.
登录
查看更多内容
影响因子：
3.8
作者：
Rajput, Ashish B.;Turbin, Dmitry A.;Cheang, Maggie C. U.;Voduc, David K.;Leung, Sam;Gelmon, Karen A.;Gilks, C. Blake;Huntsman, David G.
通讯作者：
Huntsman, David G.
DOI：
10.1158/1078-0432.ccr-16-2655
发表时间：
2017-08-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Pakish JB;Zhang Q;Chen Z;Liang H;Chisholm GB;Yuan Y;Mok SC;Broaddus RR;Lu KH;Yates MS
通讯作者：
Yates MS
影响因子：
7.3
作者：
Degos, Clara;Heinemann, Mellie;Olive, Daniel
通讯作者：
Olive, Daniel
影响因子：
3.5
作者：
Okada, Kazutake;Sadahiro, Sotaro;Suzuki, Toshiyuki
通讯作者：
Suzuki, Toshiyuki
影响因子：
9.8
作者：
Mensurado S;Rei M;Lança T;Ioannou M;Gonçalves-Sousa N;Kubo H;Malissen M;Papayannopoulos V;Serre K;Silva-Santos B
通讯作者：
Silva-Santos B