肿瘤相关巨噬细胞MGLL缺失促进免疫抑制和结直肠癌细胞腹腔种植转移  

MGLL deficiency in tumor-associated macrophages promotes immunosuppression and colorectal peritoneal metastases in mice

作　　者：袁静[1] 缪洪明[1] YUAN Jing;MIAO Hongming(Department of Biochemistry and Molecular Biology,College of Basic Medical Sciences,Army Medical University(Third Military Medical University),Chongqing,400038,China)

机构地区：[1]陆军军医大学(第三军医大学)基础医学院生物化学与分子生物学教研室,重庆400038

出　　处：《陆军军医大学学报》2023年第6期530-538,共9页Journal of Army Medical University

基　　金：国家自然科学基金面上项目(82173134)。

摘　　要：目的探究单酰甘油脂肪酶(monoacylglycerol lipase,MGLL)在肿瘤相关巨噬细胞(tumor-associated macrophages,TAMs)中调节结直肠癌腹腔种植转移(colorectal cancer peritoneal metastases,CRC-PM)的效应和机制。方法首先构建了巨噬细胞MGLL特异性敲除(conditional knockout,cKO)小鼠,并进一步构建CRC-PM模型,最后结合细胞生物学和高通量测序等方法探究肿瘤相关巨噬细胞MGLL在小鼠结直肠癌细胞腹腔种植转移中的效应和机制。结果相较于对照组小鼠,特异性敲除巨噬细胞MGLL小鼠的生存期显著缩短(P<0.05),腹腔肿瘤重量显著增加(P<0.05),同时肿瘤微环境(tumor microenvironment,TME)中T细胞占比显著减少(P<0.01)而M2型巨噬细胞占比显著增加(P<0.05),并且RNA-seq结果显示MGLL特异性敲除巨噬细胞的TRLs、PD-1/PDL-1以及HIF-1等信号通路发生显著改变。结论在结直肠癌腹腔种植转移中,肿瘤相关巨噬细胞MGLL缺失促使TAMs向M2型极化,进而抑制基于T细胞的抗肿瘤免疫,最终促进结直肠癌的腹腔种植转移。其机制可能与TRLs、PD-1/PDL-1以及HIF-1等信号通路的改变相关。ObjectiveTo investigate the effects and mechanisms of monoacylglycerol lipase(MGLL)in tumor-associated macrophages(TAMs)for the progression of colorectal cancer peritoneal metastases(CRC-PM).MethodsAfter macrophage MGLL conditional knockout(cKO)mice was constructed,a CRC-PM model was established in these cKO mice.The effects and mechanism of MGLL deficiency on TAMs were studies with cell biological and RNA-Seq assays.ResultsCompared with the control mice,macrophage MGLL deficiency significantly shortened the survival time of CRC-PC mice(P<0.05),increased the weight of peritoneal tumor masses(P<0.05),diminished the percentage of T cells in the tumor microenvironment(P<0.01),while elevated the percentage of M2 macrophages in cKO mice(P<0.05).And the results of RNA-seq showed that TRLs,PD-1/PDL-1,and HIF-1 signal pathways were significantly changed in MGLL deficiency macrophages.ConclusionIn the process of CRC-PC,MGLL deficiency leads to macrophage activation towards an M2-type phenotype and further destroys T cell-based anti-tumor immunity capacity,and ultimately promotes the progression of CRC-PC.The mechanisms may be due to the changes in TRLs,PD-1/PDL-1,and HIF-1 signal pathways.

关 键 词：肿瘤相关巨噬细胞 MGLL 结直肠癌 腹腔种植转移 

分 类 号：R392.3[医药卫生—免疫学] R73-37[医药卫生—基础医学] R735.35