GDF-15抑制NK细胞功能促进结肠癌免疫逃逸的分子机制研究

Immune microenvironment play important roles in the immune escape in colon cancer, and explore its formation mechanism is of great significance. In the previous study, we screened human colon tumor T7 phage cDNA library for proteins derived from colonic cancer cells that potentially interacted with immune cells and found GDF-15. Preliminary experiments also found that CD56brightCD16-/CD56dimCD16+ NK proportion was closely correlated with GDF-15 expression level of colon cancer patients. GDF-15 could change the phenotype of NK cells and inhibit its killing ability. Tumor tissue GDF-15 levels also associated with NK cells activity and tumor growth. Based on the above research results, we put forward the following scientific hypothesis: GDF-15 may play an important role in NK inhibition and immune escape process of colon cancer. By evaluating the correlation of GDF-15 expression level and NK polarization and colon cancer progress, clarifing the founction of GDF-15 in TINKs phenotype and function changes and discussing the molecular mechanisms of GDF-15, we intent to provide a new mechanism for TINKs mediated immune escape and a new target for colon cancer immunotherapy and experimental basis.

免疫微环境在结肠癌的免疫逃逸中起着重要作用，探索其形成机制意义重大。我们课题组前期筛选出了结肠癌免疫微环境中与免疫细胞相互作用的分子GDF-15，发现结肠癌病人外周血GDF-15水平与TINKs中不成熟NK比例及肿瘤TNM分期呈正相关，GDF-15能改变NK细胞的表型并抑制其杀伤活性，肿瘤组织GDF-15水平与NK细胞活性及肿瘤生长速度相关。基于上述研究结果，我们提出以下科学假说：肿瘤细胞分泌的GDF-15可能是结肠癌免疫微环境中诱导高细胞毒性NK向具有促免疫逃逸功能亚群极化的关键分子。本课题拟在前期工作基础上，首先系统评价GDF-15表达水平与NK极化及结肠癌进展的相关性，然后阐述GDF-15对TINKs表型和功能的影响及其在结肠癌免疫逃逸中的作用，最后深入探讨GDF-15作用的分子机制。对上述内容的探索将为TINKs介导的结肠癌免疫逃逸提供新的机制，为结肠癌的免疫治疗提供新的靶点。

免疫微环境在结肠癌的免疫逃逸中起着重要作用，探索其形成机制意义重大。我们课题组筛选出了结肠癌免疫微环境中与免疫细胞相互作用的分子GDF-15，发现结肠癌病人外周血GDF-15水平与TINKs中IL-10+NKG2D-NK比例及TNM分期呈正相关，GDF15刺激能够降低杀伤功能相关受体NKG2D、NKp30的表达，引起NK细胞活化标志CD69、C-KIT表达下调及Th1/Th2型细胞因子失衡，在体内外均诱导NK细胞表型改变并抑制杀伤功能。并进一步发现GDF-15通过上调Id2下调E2A的表达，进而抑制NK细胞关键活化性受体NKG2D的转录，从而影响NK细胞的活化与功能。上述结果首次揭示GDF-15能够通过与NK细胞相互作用，抑制其细胞毒相关分子表达与杀伤功能，并初步阐述了GDF-15通过ID2-E2A-NKG2D轴起作用的分子机制。以上研究提示了GDF15可能在诱导肿瘤免疫逃逸中的重要作用，为肿瘤的临床诊治提供新的思路和策略。