Tissue-specific immunosuppressive and proliferating macrophages fuel early metastatic progression of human colorectal cancer to liver.

Early synchronous colorectal liver metastasis (CRLM) represents a clinical condition characterized by the simultaneous presence of primary colorectal cancer (CRC) and metastatic liver lesions. In this study, we characterized the tissue-specific transcriptomes, phenotypes, and functional relevance of tumor-associated macrophages (TAMs) within the tumor microenvironment (TME) of CRC and CRLM specimens from patients who underwent simultaneous surgical removal of these malignancies. The high-throughput single-cell transcriptional analysis revealed an inverse ratio of inflammatory and immunoregulatory TAMs in the CRC and CRLM TMEs, along with heterogeneity in both tumoral tissues. Further, we found that inflammatory TAMs in CRC expressed inhibitory ligands that might support immune escape, thus favoring liver metastatic progression. In contrast, CRLM lesions possessed a highly immunosuppressive milieu characterized by large proliferative CTLA4+ immunoregulatory TAMs and by the presence of IL7R+ cytotoxic TAMs. Higher frequencies of these specific TAM subsets in CRLM were associated with shorter disease-free survival and worse patient prognosis. The identification and characterization of immunoregulatory TAMs preferentially enriched in CRLM is key for the development of novel immunotherapeutic strategies aimed at boosting anticancer immune responses within TME.