Cancer/testis Antigen MAGEA3 Interacts with STAT1 and Remodels the Tumor Microenvironment
Cancer/testis Antigen MAGEA3 Interacts with STAT1 and Remodels the Tumor Microenvironment
复制标题
癌症/睾丸抗原 MAGEA3 与 STAT1 相互作用并重塑肿瘤微环境
DOI：
10.7150/ijms.27643
复制
发表时间：
2018-01-01
影响因子：
3.6
通讯作者：
Yin, Yanhui
中科院分区：
文献类型：
--
作者：
Wang, Ying;Song, Xiao;Yin, Yanhui
癌睾丸抗原MAGEA3在睾丸和各种肿瘤中受限表达，长期以来被认为是免疫治疗的理想靶点。在本研究中，我们报道 MAGEA3 与 STAT1 相互作用并调节肿瘤细胞中酪氨酸磷酸化 STAT1 (pY-STAT1) 的表达。我们发现，当 MAGEA3 被 MAGEA3 特异性 siRNA 沉默时，pY-STAT1 显着上调。 RNA 测序分析确定了 MAGEA3 敲除细胞中 274 个 STAT1 相关基因的表达水平显着改变。进一步对这些差异表达基因进行GO富集和KEGG通路分析发现，这些差异表达基因主要富集于质膜、胞外区和MHC I类蛋白复合物，参与干扰素信号通路、免疫反应、抗原呈递和细胞趋化性。通过生物学实验验证了与趋化因子、抗原呈递和血管生成拟态形成相关的差异表达基因。基于基质胶基质的管形成测定表明，沉默肿瘤细胞中的 MAGEA3 会损害肿瘤血管生成拟态的形成。这些数据表明肿瘤细胞中MAGEA3的表达与免疫细胞浸润肿瘤微环境和抗肿瘤免疫反应相关，这意味着它可能在肿瘤免疫逃逸中发挥重要作用。我们的研究结果揭示了 MAGEA3 对免疫抑制肿瘤微环境的潜在影响，并将为提高 MAGEA3 靶向免疫治疗的疗效提供有前景的策略。
Cancer-testis antigen MAGEA3, being restrictedly expressed in testis and various kinds of tumors, has long been considered as an ideal target for immunotherapy. In this study, we report that MAGEA3 interacts with STAT1 and regulates the expression of tyrosine phosphorylated STAT1 (pY-STAT1) in tumor cells. We show that pY-STAT1 is significantly up-regulated when MAGEA3 is silenced by MAGEA3-specific siRNA. RNA sequencing analysis identified 274 STAT1-related genes to be significantly altered in expression level in MAGEA3 knockdown cells. Further analysis of these differentially expressed genes with GO enrichment and KEGG pathway revealed that they are mainly enriched in plasma membrane, extracellular region and MHC class I protein complex, and involved in the interferon signaling pathways, immune response, antigen presentation and cell chemotaxis. The differentially expressed genes associated with chemokines, antigen presentation and vasculogenic mimicry formation were validated by biological experiments. Matrigel matrix-based tube formation assay showed that silencing MAGEA3 in tumor cells impairs tumor vasculogenic mimicry formation. These data indicate that MAGEA3 expression in tumor cells is associated with immune cells infiltration into tumor microenvironment and anti-tumor immune responses, implying that it may play an important role in tumor immune escape. Our findings reveal the potential impact of MAGEA3 on the immunosuppressive tumor microenvironment and will provide promising strategies for improving the efficacy of MAGEA3-targeted immunotherapy.