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

Jing YUAN; Hongming MIAO

doi:10.16016/j.2097-0927.202209246

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

Basic Medicine | 更新时间：2026-01-09

- MGLL deficiency in tumor-associated macrophages promotes immunosuppression and colorectal peritoneal metastases in mice
- Journal of Army Medical University Vol. 45, Issue 6, Pages: 530-538(2023)
- 作者机构：
  
  400038 重庆，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
- 作者简介：
- 基金信息：
  
  the General Program of National Science Foundation of China(82173134)
- DOI：10.16016/j.2097-0927.202209246
  CLC： R392.3;R73-37;R735.35
- Received：26 September 2022，
  
  Revised：2022-10-13，
  
  Published：30 March 2023
- 稿件说明：
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Jing YUAN, Hongming MIAO. MGLL deficiency in tumor-associated macrophages promotes immunosuppression and colorectal peritoneal metastases in mice[J]. Journal of Army Medical University, 2023, 45(6): 530-538.
DOI：

Jing YUAN, Hongming MIAO. MGLL deficiency in tumor-associated macrophages promotes immunosuppression and colorectal peritoneal metastases in mice[J]. Journal of Army Medical University, 2023, 45(6): 530-538. DOI： 10.16016/j.2097-0927.202209246.

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(

0.05)，腹腔肿瘤重量显著增加(

0.05)，同时肿瘤微环境(tumor microenvironment

TME)中T细胞占比显著减少(

0.01)而M2型巨噬细胞占比显著增加(

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。

Abstract

Objective

To investigate the effects and mechanisms of monoacylglycerol lipase (MGLL) in tumor-associated macrophages (TAMs) for the progression of colorectal cancer peritoneal metastases (CRC-PM).

Methods

After 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.

Results

Compared with the control mice

macrophage MGLL deficiency significantly shortened the survival time of CRC-PC mice (

0.05)

increased the weight of peritoneal tumor masses (

0.05)

diminished the percentage of T cells in the tumor microenvironment (

0.01)

while elevated the percentage of M2 macrophages in cKO mice (

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.

Conclusion

In 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

Keywords

references

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