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

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 (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. 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.

Keywords

• tumor-associated macrophages
• monoacylglycerol lipase
• colorectal cancer
• peritoneal metastases