Low Inflammation Correlates with Protumor Tim4+TREM1+ Resident Macrophage Expansion and Limited Monocyte-Derived...

Accumulating evidence indicates that peritoneal macrophages, comprising resident peritoneal macrophages (resMØ) and monocyte-derived nonresident macrophages (moMØ), contribute to peritoneal tumor progression by promoting tumor cell proliferation and migration and driving immunosuppression. However, the mechanisms governing the expansion of resMØs and moMØs, as well as their differential contributions to the peritoneal macrophage pool in tumor-bearing mice and to tumor growth, remain to be elucidated. Using a mouse model of colorectal cancer peritoneal metastasis, induced by intraperitoneal injection of tumor organoids derived from primary tumors in genetically engineered mice carrying Apc, Kras, Tgfbr2, and Trp53 mutations, and recapitulating human-like metastatic colorectal cancer, we investigated the origin, expansion, and function of peritoneal macrophages during metastatic tumor growth. Our data support that the low inflammatory status of the peritoneal cavity during colorectal cancer peritoneal tumor growth restrains monocyte recruitment and the differentiation of Tim4- resMØs and moMØs while enabling a marked, proliferation-driven expansion of Tim4+ resMØs. Tumor-induced Tim4+ resMØs displayed a migratory and protumor transcriptomic signature characterized by the activation of genes encoding key protumorigenic molecules and potential immunotherapeutic targets, including Adora2a/Adora2b, Arg1, Ido2, Acod1, Mmp12, Cd274, Pdcd1lg2, Spp1, Trem1, and Vegfa. Correspondingly, during peritoneal colorectal cancer tumor growth, Tim4+TREM1+ resMØs migrated to the omentum, the principal peritoneal target organ for metastasis, and promoted colorectal cancer peritoneal tumor progression. These findings may help lead to the development of immunotherapies for colorectal cancer peritoneal metastasis that target tumor-associated peritoneal macrophages.