高密度脂蛋白诱导富GNAI3肠癌微囊泡增强巨噬细胞抗肿瘤作用与调控机制

The serum high density lipoprotein(HDL-C) levels showed significant correlation to the risk and prognosis of colorectal cancer and the anti-tumor ability of HDL-C may function by affecting the peritumoral microenvironment. Our previous studies revealed that HDL-C may enhance the anti-tumor ability of macrophage by affecting tumor microparticle instead of affecting macrophage directly. We also found that the HDL-induced tumor microparticles have higher content of GNAI3 protein, which can induce higher CXCL10 levels in the supernatant of macrophage. However, the molecular mechanism has not be elucidated. Therefore, we raised the questions as followed: Does HDL-C enhance the anti-tumor ability of macrophage by increasing GNAI3-rich tumor microparticle? Is it the anti-tumor ability of HDL functioned by inducing macrophage releasing CXCL10? What is the molecular mechanism of GNAI3 regulating the release of CXCL10? What is the mechanism of HDL-C regulating colorectal cancer cell enriching and involving GNAI3 into tumor microparticle? Can HDL-C enhance the benefit of immune checkpoint inhibitor PD1/PDL1 monoclonal antibody in treating colorectal cancer? This study will further elucidate the regulatory mechanism of HDL-C affecting tumor immune microenviroment and provide scientific evidence of HDL-C applying in the prevention and treatment of colorectal cancer.

血清高密度脂蛋白（HDL-C）水平与肠癌发病风险和预后明显相关，其抗肿瘤作用发挥可能通过影响肿瘤免疫微环境。前期研究表明，HDL-C增强巨噬细胞抗肿瘤功能并非通过直接作用，而是通过影响肿瘤微囊泡。此外，我们还发现用HDL-C诱导的肠癌肿瘤微囊泡（H-MP）中GNAI3含量明显升高，且H-MP所诱导的巨噬细胞上清中CXCL10等细胞因子水平升高，但分子机制有待阐明。为此，我们提出，HDL-C是否通过诱导富GNIA3的肿瘤微囊泡增强巨噬细胞抗肿瘤功能？其抗肿瘤作用发挥是否通过促进巨噬细胞分泌CXCL10等细胞因子？GNAI3调控CXCL10的分子机制是什么？HDL-C又是通过何种机制调控肠癌细胞富集GNAI3进入肿瘤微囊泡？HDL-C能否增强免疫检查点抑制剂PD1/PDL1单抗治疗肠癌的疗效？本研究的实施将进一步阐明HDL-C对肿瘤免疫微环境的调控机制，为HDL-C应用于肠癌防治提供科学依据。

血清高密度脂蛋白（HDL-C）水平与肠癌发病风险和预后明显相关，其抗肿瘤作用发挥可能通过影响肿瘤免疫微环境。本项目通过体外证实HDL-C诱导富GNAI3的肿瘤微囊泡具有增强巨噬细胞的抗肿瘤作用；确定HDL-C诱导微囊泡对巨噬细胞抗肿瘤增强作用源于囊泡中GNAI3蛋白含量增高。通过敲除母细胞中GNAI3构建无GNAI3肿瘤微囊泡，从而逆转HDL-C所诱导肿瘤微囊泡对巨噬细胞的抗肿瘤作用；证实HDL-C诱导富GNAI3的肿瘤微囊泡通过促进巨噬细胞分泌CXCL10从而增强其抗肿瘤作用并对HDL-C诱导的富GNAI3肿瘤微囊泡调控巨噬细胞CXCL10分泌升高的分子通路的进行了初步探讨。通过免疫荧光染色证实肠癌组织标本中表达CXCL10的巨噬细胞与血清HDL-C水平的相关性。通过动物实验验证HDL-C抗肿瘤及与免疫检查点抑制剂PD1/PDL1单抗协同抑制肠癌肿瘤生长的作用。该项目明确了HDL-C 通过肿瘤微囊泡调控巨噬细胞抗肿瘤功能的作用和信号通路，为 HDL-C 调控肿瘤免疫微环境的分子机制增添新的内容；为提高 HDL-C 相关的临床干预方法应用于肠癌发病预防和减少根治术后复发转移提供重要的理论基础；为 HDL-C 联合免疫检查点抑制剂 PD1/PDL1 单抗治疗肠癌提供重要依据。