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Review
. 2017 Feb 28;10(1):58.
doi: 10.1186/s13045-017-0430-2.

Tumor-associated macrophages: from basic research to clinical application

Li Yang  1   2 , Yi Zhang  3   4   5
Affiliations
Review

Tumor-associated macrophages: from basic research to clinical application

Li Yang et al. J Hematol Oncol. .

Abstract

The fact that various immune cells, including macrophages, can be found in tumor tissues has long been known. With the introduction of concept that macrophages differentiate into a classically or alternatively activated phenotype, the role of tumor-associated macrophages (TAMs) is now beginning to be elucidated. TAMs act as "protumoral macrophages," contributing to disease progression. TAMs can promote initiation and metastasis of tumor cells, inhibit antitumor immune responses mediated by T cells, and stimulate tumor angiogenesis and subsequently tumor progression. As the relationship between TAMs and malignant tumors becomes clearer, TAMs are beginning to be seen as potential biomarkers for diagnosis and prognosis of cancers, as well as therapeutic targets in these cases. In this review, we will discuss the origin, polarization, and role of TAMs in human malignant tumors, as well as how TAMs can be used as diagnostic and prognostic biomarkers and therapeutic targets of cancer in clinics.

Keywords: Biomarker; Protumoral activities; Therapeutic target; Tumor microenvironment; Tumor-associated macrophages (TAMs).

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Figures

Fig. 1
Fig. 1
The origin and polarization of TAMs in tumor microenvironments. Recruited macrophages from blood (green) and tissue-resident macrophages from the yolk sac (purple) coexist in tumors. Recruited macrophages represent the majority of TAMs. Peripheral blood monocytes are recruited locally and differentiate into macrophages in response to various chemokines and growth factors produced by stromal and tumor cells in the tumor microenvironment (CCL2, CSF1, VEGFA, CCL18, CCL20, and CXCL12). Factors that promote the polarization of TAMs to a protumor phenotype can be subdivided into those actively produced by tumor cells (microparticles, CCL2/3/4, CSF1, IL-4, IL-10), those derived from immune system components (Treg-derived IL-10, B cell-derived Igs, Th2-derived IL-4/13, and MSC-derived MFG-E8), those secreted by TAMs (MIF, IL-10, CXCL12), and those resulting from tissue stress (hypoxia, tumor-derived HMGB-1, ECM components) (orange). In addition, TAMs can also be differentiated from myeloid-derived suppressor cells in the leukemic stem cell niche
Fig. 2
Fig. 2
The effects of TAMs on tumor progression. The protumor functions of TAMs include cancer initiation and promotion (blue), immune suppression (green), metastasis, establishment of a premalignant niche (orange), and promotion of angiogenesis (purple). (1) TAMs can produce cytokines such as IL-6/IL-17/IL-23 or mitogens to induce the initiation and progression of cancer via the NF-κB or STAT3 signaling pathway in tumor cells. (2) Suppression of CTL proliferation by TAMs is at least partly dependent on metabolism of l-arginine via iNOS or arginase I, which results in ROS production. TAMs inhibit CTL responses via PD1/PD-L1 signaling pathway. TAM-derived PGE2 and IL-10 promote the induction of Tregs, and TAM-derived CCL17/18/22 recruit Tregs, which results in CTL suppression. (3) Neoplastic cell invasion of ectopic tissue can be promoted through protease-dependent ECM remodeling that may directly affect neoplastic migration or the premalignant niche. TAM-derived CCL18 promotes tumor metastasis by triggering integrin clustering and enhancing their adherence to extracellular matrix (EM) in tumor cells. TAM-derived TGF-β plays important roles in initiation and progression of the EMT. TAMs-derived TNF-α, VEGF, and TGF-β can transport through the bloodstream to destination organs, where they induce macrophages to produce S100A8, which further recruits tumor cells to these organs and promotes the formation of metastatic foci. (4) Hypoxia induces HIF-1α expression in TAMs and further regulates the transcription of many genes associated with angiogenesis. Subsets of Tie2+ TAMs can interact with mural cells/pericytes to regulate vascular structure
Fig. 3
Fig. 3
The clinical application of TAMs. As the relationship between TAMs and malignant tumors becomes clearer, TAMs are beginning to be seen as potential biomarkers for diagnosis and prognosis of cancers and as therapeutic targets in cancers. Therapeutic strategies directed at TAMs can be grouped into four areas: limiting monocyte recruitment, targeting the activation of TAMs, reprogramming TAMs to antitumor macrophages, and targeting TAMs in combination with standard therapies
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