Abstract
Tumor-associated macrophages (TAMs) are the main population of myeloid cells infiltrating solid tumors and the pivotal orchestrators of cancer-promoting inflammation. However, due to their exceptional plasticity, macrophages can be also key effector cells and powerful activators of adaptive anti-tumor immunity. This functional heterogeneity is emerging in human tumors, colorectal cancer (CRC) in particular, where the dynamic co-existence of different macrophage subtypes influences tumor development, outcome, and response to therapies. Intestinal macrophages are in close interaction with enteric microbiota, which contributes to carcinogenesis and affects treatment outcomes. This interplay may be particularly relevant in CRC, one of the most prevalent and lethal cancer types in the world. Therefore, both macrophages and intestinal microbiota are considered promising prognostic indicators and valuable targets for new therapeutic approaches. Here, we discuss the current understanding of the molecular circuits underlying the interplay between macrophages and microbiota in CRC development, progression, and response to both conventional therapies and immunotherapies.
Highlights
Beyond cancer cells, the composition of the tumor microenvironment (TME) is widely recognized as the driving force of solid tumors, influencing their development, growth, progression, and response to therapy
Most studies aimed at identifying pro-tumorigenic bacterial species have focused on strains that enrich themselves in cancer carriers (e.g., F. nucleatum, S. gallolyticus, Bacteroides fragilis, E. coli, E. faecalis) [116,117,118], colorectal cancer (CRC) dysbiosis is associated with the decrease of beneficial species (e.g., Bifidobacteria and Lactobacilli), suggesting that selective loss of anti-tumorigenic bacteria might be an additional mechanism contributing to tumor development
Confirming the tumor-promoting activity of M2-skewed macrophages, recognizable by nuclear accumulation of p50 NF-κB, we have observed in a cohort of 49 CRC patients that accumulation of p50+ Tumor-associated macrophages (TAMs) at the invasive margin is negatively correlated with M1 (IL12A) and T-helper 1 (Th1) (TBX21) gene expression and is associated with worse outcome [71]
Summary
The composition of the tumor microenvironment (TME) is widely recognized as the driving force of solid tumors, influencing their development, growth, progression, and response to therapy. Sci. 2020, 21, 6866 and nivolumab (targeting PD-1) for the treatment of metastatic melanoma, the clinical benefit of immune checkpoint blockers (ICBs) have been quickly appreciated for a growing number of cancer types, including non-small cell lung cancer, microsatellite instability-high (MSI-H) CRC, gastric cancer, Hodgkin lymphoma, head and neck squamous cell, hepatocellular, renal cancer, Merkel cell, and urothelial carcinoma [35] Despite these broad successes in several malignancies, ICBs are only useful on a small fraction of cancer patients, so the challenge at the forefront is to identify new predictors of response and understand how to overcome resistance mechanisms to enable a personalized approach of precision medicine. We examine the role of macrophages in CRC development, focusing on the main molecular determinants of their pro-tumor activity, including the gut microbiota, as well as on their prognostic and predictive significance of the response to therapy, including ICBs
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