ABSTRACT: Research based essentially on mouse models of ovarian cancer peritoneal metastasis have revealed that peritoneal macrophages, that include resident peritoneal macrophages (resMØs) and monocyte-derived non-resident macrophages, promote peritoneal tumor growth, through the induction of tumor cell proliferation and migration, and immunosuppression. However, the mechanisms controlling the expansion and differential contribution of resMØs and monocyte-derived non-resident macrophages to the pool of peritoneal macrophages present in tumor-bearing mice, and to promote tumor growth, remains to be addressed. Using a mouse model of colorectal cancer (CRC) peritoneal metastasis, based on the intraperitoneal injection of mouse tumor organoids, derived from primary tumors arising in genetically engineered mice, bearing mutations in Apc, Kras, Tgfbr2 and Trp53, and developing human-like metastatic CRC tumor growth, in the present report, the origin, expansion and function of peritoneal macrophages during peritoneal CRC tumor growth, has been investigated. Our data support that the low inflammatory status of the peritoneal cavity associated to CRC peritoneal tumor growth, restrained Ly6Chi monocyte recruitment and formation of Tim4- resMØs and moMØs, while enabling a marked cell proliferation-driven expansion of Tim4+ resMØs. Tumor-induced Tim4+ resMØs displayed a migratory and protumor transcriptomic signature, involving the activation of genes controlling the expression of important protumor molecules, such as A2A/A2B, ARG1, IDO, IL-6, IRG1, MMP12, PD-L1/2, SPP1, TREM1 and VEGFa. Correspondingly, during peritoneal CRC tumor growth, Tim4+ TREM1+ resMØs migrated to the omentum, the main peritoneal target organ for peritoneal metastasis, and promoted CRC peritoneal tumor progression.
