MAGE-C3 promotes cancer metastasis by inducing epithelial-mesenchymal transition and immunosuppression in esophageal squamous cell carcinoma.
MAGE-C3 promotes cancer metastasis by inducing epithelial-mesenchymal transition and immunosuppression in esophageal squamous cell carcinoma.
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DOI：
10.1002/cac2.12203
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发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
Zhan Q
中科院分区：
文献类型：
--
作者：
Wu Q;Zhang W;Wang Y;Min Q;Zhang H;Dong D;Zhan Q
逃避免疫监视对于肿瘤转移是必要的。因此，迫切需要更好地了解转移与肿瘤免疫逃避机制之间的相互作用。在这项研究中，我们旨在阐明食管鳞状细胞癌（ESCC）发展中肿瘤转移与免疫抑制之间的联系的新机制。使用免疫组织化学检测黑色素瘤相关抗原 C3 (MAGE-C3) 的表达。 Transwell实验用于评估食管鳞状细胞癌（ESCC）细胞的迁移和侵袭能力。使用小鼠的转移测定来评估体内转移能力。进行淋巴细胞介导的细胞毒性测定以可视化对肿瘤细胞的免疫抑制功能。进行 RNA 测序以确定 MAGE-C3 过表达 ESCC 细胞和对照细胞之间的差异表达基因。进行基因本体 (GO) 富集分析，以确定受 MAGE-C3 影响最大的改变途径。使用蛋白质印迹、GAS 荧光素酶报告基因测定、免疫荧光和流式细胞术分析干扰素-γ (IFN-γ) 通路的激活。通过蛋白质印迹和免疫沉淀确定 MAGE-C3 在 IFN-γ 通路中的作用。此外，免疫组织化学和流式细胞术分析监测了小鼠肺转移瘤中浸润 T 细胞群的变化。 MAGE-C3 在 ESCC 组织中过度表达。 MAGE-C3的高表达与ESCC患者的淋巴转移风险和较差的生存率显着相关。功能实验表明，MAGE-C3通过激活上皮间质转化（EMT）促进肿瘤转移。 MAGE-C3 抑制抗肿瘤免疫并调节 T 细胞的细胞因子分泌，表明具有免疫抑制功能。从机制上讲，MAGE-C3 通过与 IFN-γ 受体 1 (IFNGR1) 结合并加强 IFNGR1 与信号转导子和转录激活剂 1 (STAT1) 之间的相互作用，促进 IFN-γ 信号传导并上调程序性细胞死亡配体 1 (PDL1)。有趣的是，MAGE-C3 在免疫功能正常的小鼠中比在免疫缺陷的裸鼠中表现出更高的肿瘤发生率，证实了 MAGE-C3 的免疫抑制作用。此外，携带 MAGE-C3 过度表达肿瘤的小鼠表现出较差的生存率和更多的肺转移，同时 CD8+ 浸润 T 细胞减少，程序性细胞死亡 1 (PD-1)+CD8+ 浸润 T 细胞增加。 MAGE-C3通过促进EMT和保护肿瘤免受免疫监视来增强肿瘤转移，并可能成为潜在的预后标志物和治疗靶点。我们的结果表明，MAGE-C3 不仅通过 EMT 促进肿瘤转移，还通过保护肿瘤免受免疫监视来促进肿瘤转移
Evading immune surveillance is necessary for tumor metastasis. Thus, there is an urgent need to better understand the interaction between metastasis and mechanisms of tumor immune evasion. In this study, we aimed to clarify a novel mechanism that link tumor metastasis and immunosuppression in the development of esophageal squamous cell carcinoma (ESCC). The expression of melanoma‐associated antigen C3 (MAGE‐C3) was detected using immunohistochemistry. Transwell assays were used to evaluate the migration and invasion ability of esophageal squamous cell carcinoma (ESCC) cells. Metastasis assays in mice were used to evaluate metastatic ability in vivo. Lymphocyte‐mediated cytotoxicity assays were performed to visualize the immune suppression function on tumor cells. RNA sequencing was performed to identify differentially expressed genes between MAGE‐C3 overexpressing ESCC cells and control cells. Gene ontology (GO) enrichment analyses was performed to identify the most altered pathways influenced by MAGE‐C3. The activation of the interferon‐γ (IFN‐γ) pathway was analyzed using Western blotting, GAS luciferase reporter assays, immunofluorescence, and flow cytometry. The role of MAGE‐C3 in the IFN‐γ pathway was determined by Western blotting and immunoprecipitation. Furthermore, immunohistochemistry and flow cytometry analysis monitored the changes of infiltrated T cell populations in murine lung metastases. MAGE‐C3 was overexpressed in ESCC tissues. High expression of MAGE‐C3 had a significant association with the risk of lymphatic metastasis and poor survival in patients with ESCC. Functional experiments revealed that MAGE‐C3 promoted tumor metastasis by activating the epithelial‐mesenchymal transition (EMT). MAGE‐C3 repressed antitumor immunity and regulated cytokine secretion of T cells, implying an immunosuppressive function. Mechanistically, MAGE‐C3 facilitated IFN‐γ signaling and upregulated programmed cell death ligand 1 (PDL1) by binding with IFN‐γ receptor 1 (IFNGR1) and strengthening the interaction between IFNGR1 and signal transducer and activator of transcription 1 (STAT1). Interestingly, MAGE‐C3 displayed higher tumorigenesis in immune‐competent mice than in immune‐deficient nude mice, confirming the immunosuppressive role of MAGE‐C3. Furthermore, mice bearing MAGE‐C3‐overexpressing tumors showed worse survival and more lung metastases with decreased CD8+ infiltrated T cells and increased programmed cell death 1 (PD‐1)+CD8+ infiltrated T cells. MAGE‐C3 enhances tumor metastasis through promoting EMT and protecting tumors from immune surveillance, and could be a potential prognostic marker and therapeutic target. Our results identified that MAGE‐C3 promotes tumor metastasis not only through the EMT but also by protecting tumors from immunosurveillance
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影响因子：
21.3
作者：
Singh S;Kumar S;Srivastava RK;Nandi A;Thacker G;Murali H;Kim S;Baldeon M;Tobias J;Blanco MA;Saffie R;Zaidi MR;Sinha S;Busino L;Fuchs SY;Chakrabarti R
通讯作者：
Chakrabarti R
DOI：
10.1038/s41577-019-0218-4
发表时间：
2020-01
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Kalbasi A;Ribas A
通讯作者：
Ribas A
影响因子：
64.8
作者：
Tauriello, Daniele V. F.;Palomo-Ponce, Sergio;Batlle, Eduard
通讯作者：
Batlle, Eduard
影响因子：
2.9
作者：
Jia, Binghan;Zhao, Xiaoling;Yang, Yuemei
通讯作者：
Yang, Yuemei
影响因子：
13.6
作者：
Tacer, Klementina Fon;Montoya, Marhiah C.;Potts, Patrick Ryan
通讯作者：
Potts, Patrick Ryan