Origin and Functions of Tumor-Associated Myeloid Cells (TAMCs)

Abstract

The construction of an inflammatory microenvironment provides the fuel for cancer development and progression. Hence, solid tumors promote the expansion and the recruitment of leukocyte populations, among which tumor-associated myeloid cells (TAMCs) represent a paradigm for cancer-promoting inflammation. TAMCs group heterogeneous phagocytic populations stemming from a common myeloid progenitor (CMP), that orchestrate various aspects of cancer, including: diversion and skewing of adaptive responses; immunosuppression; cell growth; angiogenesis; matrix deposition and remodelling; construction of a metastatic niche and actual metastasis. Several evidence indicate that TAMCs show plasticity and/or functional heterogeneity, suggesting that tumour-derived factors promote their functional "reprogramming" towards protumoral activities. While recent studies have attempted to address the role of microenvironment signals, the interplay between cancer cells, innate and adaptive immunity is now emerging as a crucial step of the TAMCs reprogramming. Here we discuss the evidence for the differentiation of TAMCs during the course of tumor progression and the molecular mechanisms that regulate such event.

Fig. 1

Mechanisms of differentiation and accumulation of TAMCs. In the bone marrow hematopoietic stem cell (HSC) differentiate into common myeloid progenitors (CMPs), which can subsequently differentiate into granulocyte/macrophage progenitors (GMPs). GMPs give rise to different subsets of circulating cells: monocytes (Mo), Tie2-expressing monocytes (TEM), neutrophils (PMN), and granulocytic and monocytic myeloid-suppressor cells (G-MDSC and M-MDSC). Tumors secrete factors which sustain myelopoiesis, promote the recruitment of circulating cells into both the tumor mass or secondary lymphoid organs (lymph nodes and spleen) and orientate their functional differentiation to their own advantage. TAMs are recruited into the tumor site by chemotactic factors (eg. CCL2, CSF-1) and represent the prominent phagocytes population orchestrating cancer-related inflammation. TEMs derive from circulating Tie2⁺ monocytes and are recruited in tumors by hypoxia-inducible chemoattractants, such as Ang2 and CXCL12. Tumor-associated neutrophils (TANs) stem from circulating neutrophils and are recruited in tumors by chemokines (e.g. CXCL8). TANs participate in tumor promotion by the expression of crucial pro-angiogenic factors. During tumour progression an heterogeneous population of myeloid cells (G-MDSC and M-MDSC) accumulate in blood and lymphoid organs. MDSCs may be recruited by selected chemoattractants (CCL2, S-100, VEGF, C5a) into the tumor microenvironment, where they contribute to suppression of the adaptive immunity

Fig. 2

Pathways of polarized activation of tumor associated myeloid cells (TAMCs). As depicted, TAMCs reciprocally influence their protumoral differentiation, under the “remote control” of cancer-associated fibroblasts (CAFs), T and B lymphocytes. TAMs in concert with Tregs and tumor cells, produce TGFβ that induces the alternative (N2) activation of TANs. Differentiation of MDSCs is modulated by several tumor-derived factors, including GM-CSF, IL-6, VEGF and PGE2. Further, tumor microenvironmental signals can convert MDSCs in endothelial cells (ECs) or in TAMs, the latter event mainly regulated by hypoxia. Hypoxic ECs up-regulate Ang-2 that enhances activation of pro-angiogenic and M2-skewed TEMs