The majority of basic and clinical studies have shown a protumor function of tumor-associated macrophages (TAMs), which represent a large proportion of matrix cells. TAMs promote tumorigenesis, and their number is related to the malignancy degree and poor prognosis of many kinds of tumors. Macrophage plasticity makes it possible to change the tumor microenvironment and remodel antitumor immunity during cancer immunotherapy. Increasing numbers of studies have revealed the effects of TAMs on the tumor microenvironment, for example, via promotion of tumor growth and tumorigenesis and through an increase in the number of cancer stem cells or via facilitation of angiogenesis, lymphangiogenesis, and metastasis. Investigators also proposed tumor-immunological treatments targeting TAMs by inhibiting TAM recruitment and differentiation, by regulating TAM polarization, and by blocking factors and pathways associated with the protumor function of TAMs. This comprehensive review presents recent research on TAMs in relation to prediction of poor outcomes, remodeling of the tumor immune microenvironment, and immunological targeted therapies.
Macrophages are differentiated cells of the mononuclear phagocytic lineage. They are heterogeneous cells with distinct functions and respond differently to various microenvironmental signals and thus have distinct functions. Macrophages—derived from hematopoietic stem cells in bone marrow or from progenitor cells in the embryonal yolk sac—differentiate into two distinct types of macrophages (M
TAMs provide a suitable microenvironment for tumor invasion and progression and contribute to the metastasis of tumor cells [
TAMs associated with poor prognosis.
Cancer | IHC marker | Prognostic outcome | Ref. |
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Hormone receptor-positive breast cancer | Intratumoral TAMs | Poor DFS | [ |
Triple-negative breast cancer | CD68+ TAMs | Poor OS and DFS | [ |
Gastric cancer | CD204+ TAMs combined with Osteopontin (OPN) | Poor 5-year OS | [ |
Lung cancer induced malignant pleural effusion (MPE) | CD163+ TAMs in MPE | Poor progression-free survival | [ |
Non-small cell lung cancer | TAMs combined with OPN | Lower DFS and OS | [ |
TAMs combined with IL-6, CSF-1 | Lower 5-year survival rate | [ | |
Esophageal cancer undergoing neoadjuvant chemotherapy | CD68+ and CD163+ TAMs | Tumor depth, lymphatic invasion, venous invasion, and poor response to chemotherapy | [ |
Oral squamous cell carcinoma | CD68+ TAMs or combined with ALDH1, CD44, SOX2, IL-10 | High tumor grade, lymph node metastasis, shorter OS and DFS, and poor clinical stage | [ |
Nonfunctional pancreatic neuroendocrine tumors (NF-PNETs) | CD68+ TAMs combined with Ki-67 index | High risk of recurrence | [ |
Glioma | CD206+ TAMs | Lower PFS and OS | [ |
Colorectal cancer | CD40+ TAMs or combined with urokinase-type plasminogen activator receptor | Lower OS, lymph node, and distant metastasis | [ |
Pancreatic ductal adenocarcinoma | CD204+ TAMs combined with CD44/CD133 | Lower PFS and OS | [ |
Advanced epithelial ovarian cancer | CD68+ and CD163+ TAMs | Poor PFS and OS | [ |
Bladder carcinoma | CD68+ TAMs | Poor recurrence-free survival | [ |
Triple-negative endometrial endometrioid adenocarcinoma | CD68+ TAMs combined with overexpression of EGFR | Poor OS | [ |
Prostate cancer | CD68+ TAMs | Poorly differentiated disease but no association with biochemical recurrence after radical prostatectomy | [ |
Poor OS | [ | ||
Classical Hodgkin lymphoma | CD68+ and CD163+ TAMs | High risk of treatment failure with ABVD chemotherapy | [ |
Primary central nervous system lymphoma (PCNSL) | CD68+ and CD163+ TAMs | Inferior PFS but no association with OS | [ |
Peripheral T-cell lymphoma | CD68+ TAMs combined with VEGF | Poor OS | [ |
Diffuse large B-cell lymphoma | CD68+ TAMs | Poor treatment outcome and poor median survival time | [ |
PFS: progression-free survival, DFS: disease-free survival, and OS: overall survival.
Chemotherapy is a conventional treatment modality for cancer patients. Although chemotherapies have strong effects on some kinds of tumors, such as small cell lung cancer [
TAMs were found to help reduce the effects of chemotherapy. Infiltration by CD68+ and CD163+ TAMs is associated with a poor response to chemotherapy in patients with esophageal cancer [
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are novel treatments of lung cancer with EGFR mutation and have higher specificity and fewer side effects than traditional treatments; M2-polarized TAMs also correlate with the decreased responsiveness to EGFR-TKI treatment in patients with advanced lung adenocarcinoma [
Radiotherapy (RT) is a localized therapy that is highly effective at killing primary tumor cells located within the field of the radiation beam. Despite sophisticated techniques for radiation delivery as well as the combination of radiation with chemotherapy, tumors can recur [
TAMs are abundantly recruited to tumors after irradiation and may modulate cancer cells’ responses to therapy [
The tumor immune microenvironment is mainly formed by such immune cells as macrophages, T lymphocytes, natural killer cells (NK cells), dendritic cells, neutrophils, and myeloid-derived suppressor cells (MDSCs) [
Cancer can be considered a nonresolving inflammatory disease. Up to 20% of all cancers arise in association with chronic inflammation, and almost all solid tumors contain inflammatory infiltrates [
Metastasis is responsible for more than 90% of cancer mortality yet remains the least understood stage of tumor progression. TAMs have been shown to be key players in metastasis and mainly participate in several steps including epithelial-to-mesenchymal transition (EMT), local invasion and intravasation into the vasculature, transit through the circulatory system, extravasation and seeding in the premetastatic niche, and finally survival and growth at the metastatic site [
In breast tumors, TAMs are recruited to pulmonary metastases by CCL2 and enhance extravasation, seeding, and persistent growth of tumor cells in part via expression of VEGF [
EMT is a process via which epithelial tumor cells lose epithelial features and gain mesenchymal phenotypes [
CCL18 released from TAMs can induce EndMT in endothelial cells to produce a different differentiated phenotype, which may lead to a loss of cell-cell junctions as well as enhanced invasiveness and migratory capacity [
The growth and spread of neoplasms depend on angiogenesis and lymphangiogenesis in the tumor microenvironment. With neoplastic progression, increasing numbers of blood and lymphatic vessels provide supply channels for tumor tissues. On the other hand, it is reported that these mounting vessels provide a route for the lymph-nodal and distant metastases of tumor cells [
Coordination of the lymphatic microvascular network with the blood microvasculature is involved in normal physiological functions, such as local tissue fluid balance, tissue perfusion, and immune surveillance [
Tumor cells induce formation of lymphatic vessels via the lymphatic system metastasis through VEGF-C, VEGF-D, and other cytokines [
CSCs or cancer-initiating cells are defined as a small subpopulation of cancer cells with the capacity for self-renewal and pluripotency. CSCs are necessary for initiation of new tumor growth at distant sites. Currently, many studies support the notion that CSCs, which have many features of stem cells, are responsible for the poor prognosis of patients by promoting tumor recurrence and metastasis [
TAMs can regulate the plasticity of CSC phenotypes and functions. Recently, some of TAMs-CSCs interrelations were confirmed experimentally. TAMs were found to release milk-fat globule EGF-VIII, which activates the CSC-specific pathways—STAT3, Hedgehog, and Sonic—and strongly amplifies drug resistance and tumorigenicity of CSCs [
The functional and phenotypic heterogeneity of CSCs themselves in turn affects the pathophysiological activities of TAMs. It seems that active CSCs should be able to promote the M1-to-M2 conversion, induce formation of new vasculature via VEGF release, and build CSC-protective niches via tissue-repair pathways [
TAMs promote tumor progression.
TAMs can be considered a biomarker of poor prognosis and reduce the curative effect of chemotherapy and radiotherapy. In terms of mechanisms, TAMs may promote a tumor immunosuppressive microenvironment, tumorigenesis, angiogenesis, and lymphangiogenesis and can facilitate metastasis.
Immunotherapy acts in a fundamentally different way in comparison with classical therapies. Rather than destroying tumor cells directly, immunotherapy promotes tumor cell killing via the immune response of the host. This result can be achieved directly via the main effectors of the immune system, such as macrophages. Evidence reviewed by Mills et al. indicates that modulation of macrophage responses is a breakthrough that will facilitate successful immunotherapy [
Immunotherapies targeting TAMs.
Therapeutic approaches | Cancer | Drugs | Ref. |
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Blocking the murine or human IL-4 receptor |
— | RNA aptamer | [ |
Inducing apoptosis in TAMs via Kv1.3 and Kv1.5 potassium channels | — | Membrane-permeant drugs | [ |
Selectively cytotoxic for TAMs and their circulating precursors (monocytes) by activating caspase 8-dependent apoptosis | Sarcoma and ovarian carcinoma | Trabectedin | [ |
Reducing macrophage motility, inhibiting macrophage infiltration of irradiated tumors | Colon carcinoma | Dequalinium-14 | [ |
Suppressing of tumor-associated macrophage differentiation | Gallbladder cancer | Interferon- |
[ |
|
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Reversing TAM orientation and polarization from M2- to M1-type TAMs | Breast cancer | Dimethyl sulfoxide | [ |
Reeducating CD163+ TAMs to M1 macrophages through TLR4-mediated pathway | MPE | PA-MSHA | [ |
Shifting the M1/M2 TAMs balance by M-CSFR signaling blockade | Lung carcinoma and breast carcinoma | Anti-M-CSFR antibody | [ |
Modulating the M2/M1 macrophage ratio | Lung cancer | IFN |
[ |
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Inhibiting the paracrine loop between TAM and PCa cells via NF- |
Prostate cancer | Somatostatin derivate (smsDX) | [ |
Suppressing chemokine (C-C motif) ligand 2 expression in tumor-associated macrophage | Lung carcinoma | Luteolin | [ |
Inhibiting macrophage-induced EMT by downregulation of EGFR pathway | Non-small cell lung cancer | Cannabinoid receptor-2 agonist | [ |
Strategies to deplete TAMs have been successful in experimental settings and are now considered a promising therapeutic approach in the clinic [
An RNA aptamer that blocks the murine or human IL-4 receptor-
TAMs are typically designated as “alternatively activated” noninflammatory M2-type macrophages, in contrast to the “classically activated” inflammatory M1 type. TAMs coexist with tumors and function as an accomplice in the promotion of tumor progression, especially after being programmed and polarized into a proangiogenic/immunosuppressive (M2-like) phenotype by the tumor microenvironment [
The ability of TAMs to accelerate vessel growth is mediated by increased secretion of several proangiogenic factors. Therapeutic success in blocking these protumor activities in preclinical models and early clinical trials highlighted macrophages as effective targets of combination cancer therapy [
TAMs comprise an important part of the tumor microenvironment, and their mobilization into the tumor microenvironment plays a key role in malignant progression. Studies have shown that TAMs lead to a poor clinical prognosis and promote progression of various tumors; these cells also correlate with an unfavorable outcome following therapy. After accumulation in tumor tissues, TAMs can remodel the tumor microenvironment to promote matrix remodeling and promote tumor growth and increase angiogenesis CSC-associated tumor progression. With rapid progress in the understanding of TAM functions, new therapeutic approaches against tumors have been developed, such as inhibition of TAM recruitment or suppression of TAM survival, regulation of TAM polarization, reprogramming of TAMs into the antitumor M1 phenotype, and blocking of factors and pathways associated with the protumor function of TAMs. Thus, the increasing knowledge about the biological effects of TAMs and the tumor microenvironment may lead to novel cancer therapies.
The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
The authors declare that they have no competing interests.
Qiujun Guo, Zhichao Jin, and Yuan Yuan contributed equally to this work.
This work was supported by the National Twelfth Five-Year Plan for Science and Technology Support Program of China (no. 2014BAI10B01) and the National Natural Science Foundation of China (nos. 81202656, 81273718, 81403346, and 81603610).