MFG-E8通过诱导肿瘤相关巨噬细胞极化促进胃癌免疫抑制性微环境的形成及不良预后的机制研究

Gastric cancer is one of the most common malignant tumors in the world. Immunotherapy is considered to be the most promising in the field of cancer treatment. However, in the study of gastric cancer, only a small number of people have benefited. Exploring the unique immunosuppressive mechanism and guiding treatment in gastric cancer has become an urgent problem to be solved. We previously found that MFG-E8 is highly expressed in gastric cancer tissues and is an independent prognostic factor, which was confirmed in four independent cohorts of GSE15459, GSE62254, GSE 15460 and TCGA (all four groups P < 0.0001). Considering literature reports, we hypothesized that MFG-E8 can promote the formation of tumor immunosuppressive microenvironment, tumor invasion, and immune escape by tumor-associated macrophages M2 polarization. The preliminary results analysis confirmed that MFG-E8 was positively correlated with M2 markers and immunosuppressive microenvironment of macrophages such as CD14, TGM2, MRC1 and Foxp3. Therefore, this project plans to clarify the effect of MFG-E8 on the malignant phenotype of gastric cancer, and whether it promotes the M2 polarization of tumor-associated macrophages and the formation of tumor immunosuppressive microenvironment, and mapping related secretory proteins. This work aims to provide new ideas for the treatment of gastric cancer.

胃癌是全球范围内最常见恶性肿瘤之一。免疫逃逸相关治疗在肿瘤治疗领域被认为是最有前景的治疗方式，但在胃癌的研究中，仅有极少部分人能够取得获益。探寻在胃癌中特有的免疫抑制机制并指导治疗成为亟待解决的问题。我们前期发现MFG-E8在胃癌组织中高表达，且是独立的预后不良因素，这在TCGA等四个队列中均得到证实（所有四组P<0.0001）。综合文献报道，我们猜测MFG-E8可通过促进肿瘤相关巨噬细胞M2极化发挥促进肿瘤免疫抑制微环境形成并促进肿瘤侵袭、浸润、免疫逃逸。前期结果分析证实MFG-E8与CD14、TGM2、MRC1、Foxp3等巨噬细胞M2标志物及免疫抑制微环境标志物显著正相关。因此，本课题计划明确MFG-E8对胃癌恶性表型的影响，阐述其是否促进肿瘤相关巨噬细胞M2极化、肿瘤免疫抑制微环境形成，并探讨涉及通路、绘制相关分泌蛋白网络图、探索逆转上述过程的相关药物，为胃癌治疗提供新的思路。

胃癌是全球范围内最常见恶性肿瘤之一。免疫逃逸相关治疗在胃癌肿瘤治疗领域被认为是最有前景的治疗方式，前期研究证实仅有极少部分胃癌患者为真正的“热肿瘤”并从免疫治疗中直接获益，探寻在胃癌中特有的免疫抑制机制并指导治疗成为亟待解决的问题。我们前期发现MFG-E8在胃癌组织中高表达，且是独立的预后不良因素，猜测MFG-E8可通过促进肿瘤相关巨噬细胞M2极化发挥促进肿瘤免疫抑制微环境形成并促进肿瘤侵袭、浸润、免疫逃逸。.本课题围绕上述假说，先后开展MFG-E8在临床队列、胃癌肿瘤细胞系等体内、体外研究探索，但未证实前期猜测。课题组进一步开展针对196例胃癌患者的蛋白组学数据深度挖掘，探讨胃癌患者蛋白组学层面的免疫三种亚型，提出新的分子靶标。此外，研究发掘DNA损伤通路、HER2耐药的再挑战也是胃癌领域治疗最为关注的热点问题，针对以上内容均开展进一步的探索。