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Macrophage Polarity and Cancer
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This entry is adapted from the peer-reviewed paper 10.3390/ijms23010144

Macrophages are present in most human tissues and have very diverse functions. Activated macrophages are usually divided into two phenotypes, M1 macrophages and M2 macrophages, which are altered by various factors such as microorganisms, tissue microenvironment, and cytokine signals. Macrophage polarity is very important for infections, inflammatory diseases, and malignancies; its management can be key in the prevention and treatment of diseases. 

cell-cell interaction microenvironment monocytes M1 M2 tumor-associated macrophages

1. Introduction

In 1892, microbiologist Ilya Metchnikov discovered cells that move around and eat things and termed these as macrophages [1]. There have been many studies on the origin of macrophages, and the concept of the mononuclear phagocyte system was proposed by Furth and Cohn in 1968 [2]. Monocytes are thought to emerge from bone marrow-derived precursors, drift into the circulatory system, and migrate to peripheral tissues as needed. Although this hypothesis has been believed for a long time, some tissue-indigenous macrophages have been reported to originate from the yolk sac during embryogenesis and are maintained independently of monocytes [3][4]. These facts indicate that tissue macrophages can be divided into two groups: those derived from the yolk sac during embryonic life and those derived from bone marrow precursors. However, it is still unclear what the exact functions of macrophages are, as well as if there are differences between yolk sac-derived and bone marrow-derived macrophages. In addition, some tissues have specialized macrophages, such as central nervous system microglia, bone osteoclasts, alveolar macrophages in the lungs, and Kupffer cells in the liver—all of which play an important role in maintaining tissue homeostasis [5]. Monocytes are a bone marrow-derived population that make up about 5–10% of white blood cells, and most macrophages are altered monocytes [6]. Monocytes have a lifespan of approximately two days, but this lengthens to several months when they migrate into tissues and change into macrophages, allowing them to function for a long time [6]. Macrophages are often responsible for the host defense against microorganisms by exerting immune functions, but they are also closely associated with autoimmune diseases and malignant tumors [5].

2. Cancer and Macrophages

In cancer tissue, there are numerous immune cells, fibroblasts, and epithelial cells, which comprise the tumor microenvironment (TME) and are closely involved in the growth and progression of cancer cells [7]. Cancer cells secrete monocyte chemotactic factors (mainly CCL2) to recruit monocytes/macrophages to the TME [8]. In many cases, macrophages express M1-type markers and exert anticancer effects with other immune cells, but in the TME, they are in an unusual state [9]. These macrophages are called TAMs, which secrete angiogenic and immunosuppressive factors, as well as promote tumor growth, invasion, and metastasis through tissue destruction and remodeling [9].
Macrophages are pluripotent immune cells and therefore secrete a large number of cytokines [8]. TAMs often express M2 macrophage markers such as CD163 and CD206 [10]. Recently, however, some TAMs were found to express both M1 and M2 markers. M1-type TAMs were even found to contribute to tumor progression, so it is no longer correct to assume that TAMs are always M2 macrophages [11]. TAMs suppress antitumor immunity as well as promote angiogenesis, tumor growth, tumor invasion, and metastasis [9][12].

2.1. Cancer Progression Mechanism of TAMs

Cancer cells secrete a variety of factors that induce TAMs by activating AKT/mTOR and ERK/STAT3 signaling [13][14]. TAMs secrete cell growth factors such as TNF-α, TGF-β, epidermal growth factor (EGF), and platelet-derived growth factor, which induce cancer tissue growth [9][12]. Activation of EGF/STAT3 signaling and TNF-α/nuclear factor-kappa B signaling by TAMs promotes tumor growth and progression [15]. Angiogenesis is a very important process in supplying nutrients to tumors and creating pathways for metastasis [16]. TAMs secrete a variety of angiogenic factors, especially vascular endothelial growth factor, which has a strong effect and is a therapeutic target in many cancers [16][17].
Among the different cytokines, chemokines are leukocyte chemotactic factors of relatively small molecular weight, but they are also important in TME [18]. Inhibition of CCL2 is important because CCL2 produced by cancer cells recruits macrophages to the TME and directly increases the metastatic potential of cancer cells [19][20]. The regulation of chemokines in TME is important because TAMs also produce chemokines that act on cancer cells, immune cells, and stromal cells [21][22].
In recent years, the focus of drug therapy for cancers such as lung cancer, kidney cancer, and melanoma has shifted to immune checkpoint inhibitors [23][24][25]. Most immune checkpoint inhibitors target the programmed death receptor-1-programmed cell death ligand-1 (PD-L1) axis. However, TAMs are also becoming increasingly important in cancer therapy; these suppress cytotoxic T cells by secreting PD-L1 and induce Treg by secreting IL-10 [26]. Furthermore, TAMs may maintain tumor immunosuppressive capacity by increasing PD-L2 secretion when PD-L1 is suppressed [27]. CD25, which has a high affinity for IL-2, is abundantly expressed on the surface of Treg. When CD25 is consumed by IL-2, it inhibits the activation of antigen-presenting cells [28].
They decrease anti-tumor immunity by suppressing cytotoxic T cells and natural killer cells by secreting bone marrow-derived suppressor cells (MDSCs), ARG-1, iNOS, and IL-10 [29].
Two main types of MDSCs have been reported: monocyte-like and granulocyte-like [29]. Monocyte-like MDSCs can be recruited to cancer tissues by chemokines and can also be converted to TAMs in hypoxic environments, thus MDSCs are a source of TAMs [29][30]. Thus, TAMs play a central function in TME, and their regulation and suppression are very important in cancer therapy.

2.2. Regulation and Cancer Therapy for TAMs

It is clear from previous reports that TAMs suppress antitumor immunity and promote tumor growth and progression. Therefore, many cancer therapies targeting TAMs have been investigated (Table 1). One of the targets of TAM control is the CCL2–CCR2 axis [21]. CCL2 secreted by cancer cells is a typical monocyte/macrophage chemotactic factor that strongly recruits macrophages to the TME [20]. Therefore, inhibition of the CCL2–CCR2 axis may reduce the supply of TAMs to the TME. CCL2 may also be an important therapeutic target because it acts directly on tumor cells to promote tumor growth, progression, and resistance to chemotherapy [19]. Propagermanium, a drug for chronic hepatitis B, acts by inhibiting CCL2, and it is currently being studied for use in breast cancer [31]. Blocking antibodies against CCL2 have been clinically studied in prostate cancer, but inhibition of the CCL2–CCR2 axis leads to a decrease in monocytes and an increase in CCL2 levels rather than a therapeutic response [32]. Meanwhile, the CCR2 inhibitor PF-04136309 was used in combination with chemotherapy for pancreatic cancer but did not show sufficient efficacy [33]. Currently, a drug (BMS-813160) that is expected to suppress both CCR2 and CCR5 and inhibit the mobilization of TAMs to the TME is also under clinical investigation (NCT03767582).
Table 1. Drugs targeting TAMs.
Table
Drug Drug Type Target Factor Clinical Trial Number Tumor
PF-04136309 CCR2 inhibitor CCL2–CCR2 NCT02732938
NCT01413022		 PDAC
PDAC
CNTO 888 CCL2 antibody CCL2–CCR2 NCT00992186 CRPC
BMS-813160 CCR2/5 inhibitor CCL2–CCR2/5 NCT03184870
NCT03496662
NCT03767582
NCT04123379		 PDAC, CRC
PDAC
PDAC
NSCLC, HCC
PLX-3397 CSF-1R inhibitor CSF-1R NCT02452424
NCT02777710		 Melanoma, NSCLC, etc.
PDAC, CRC
RG-7155 CSF-1R inhibitor CSF-1R NCT02323191
NCT01494688
NCT02760797		 Melanoma, TNBC, etc.
TNBC, CRC, etc.
TNBC, CRC, etc.
AMG-820 CSF-1R inhibitor CSF-1R NCT02713529 PDAC, NSCLC
BMS-986253 CXCL8 antibody CXCL8–CXCR1/2 NCT03689699
NCT04050462
NCT04123379		 HSPC
HCC
NSCLC, HCC
AZD5069 CXCR2 antagonist CXCL8–CXCR1/2 NCT03177187 CRPC
RO7009789 CD40 agonist CD40 NCT02588443 PDAC
Hu5F9-G4 CD47 antibody CD47 NCT02953509 Non-Hodgkin’s Lymphoma
IPI-549 PI3Kγ inhibitor PI3Kγ NCT03961698
NCT02637531		 TNBC, RCC
NSCLC, TNBC, etc.
TMP195 Class IIa HDAC inhibitor Class IIa HDAC None None
Trabectedin small molecule Caspase 8 None None
Zoledronate small molecule NA None one
CCR, CC chemokine receptor; CCL, CC chemokine ligand; PDAC, pancreatic ductal adenocarcinoma; CRPC, castration-resistant prostate cancer; CRC, colorectal cancer; NSCLC, non-small cell lung cancer; HCC, hepatocellular carcinoma; CSF-1R, colony-stimulating factor-1 receptor; CXCL, CXC chemokine ligand; CXCR, CXC chemokine receptor; CD, cluster of differentiation; PI3k, phosphoinositide 3-kinase; TNBC, triple-negative breast cancer; HDAC, histone deacetylase.
 
Colony-stimulating factor 1 receptor (CSF-1R) is a very important factor in macrophage differentiation [34]. CSF-1 and IL-34 have been identified as CSF-1R ligands, and they are also potential targets for therapy [35]. Many drugs targeting CSF-1R have been developed and are currently under clinical investigation [36]. Pexidartinib has demonstrated good therapeutic efficacy as a single agent in tenosynovial giant cell tumors [37]. However, the therapeutic effect of CSF-1R inhibitors alone may be inadequate, and the mobilization of MDSCs into TME as a compensatory effect has been suggested as a possible cause [38]. For this reason, combination therapy of CSF-1R inhibitors with other anticancer agents and immune checkpoint inhibitors is being studied.
As another approach to TAM regulation, CD47, which signals to avoid phagocytosis from macrophages, could be a target [39]. In fact, anti-CD47 antibodies, in combination with anti-CD20 antibodies, have shown good therapeutic efficacy against non-Hodgkin’s lymphoma [40]. Trabectedin has also been reported to induce caspase-8-mediated apoptosis in TAMs, whereas zoledronic acid inhibits TAM differentiation [41][42]. Macrophages are becoming increasingly important in cancer therapy, and research into their regulation is ongoing.

3. Conclusions

Macrophages are widely distributed in the human body and exert various functions to influence a wide range of diseases such as infectious diseases, malignant tumors, and inflammatory diseases (Figure 1). Therefore, it is becoming increasingly important to understand the state and polarity of macrophages, as their regulation can be a therapeutic target. Specifically, it may enable survival from COVID-19 and HIV viruses, suppression of inflammation, and inhibition of tumor progression. Various indications for targeted therapeutic agents against macrophages are still being investigated, but none of them can completely control macrophages. In other words, there are many factors that affect macrophages, and it may be very difficult to control them with a few factors. Therefore, further research in this field, including macrophages as well as other immune cells, is important.
Ijms 23 00144 g002
Figure 1. Positive and negative roles of macrophages. Macrophages exert antitumor effects but can act to promote tumor progression. Macrophages exert antimicrobial effects but can be targets of viruses and cause cytokine storms. Macrophages are responsible for tissue repair and metabolic control but can also cause tissue destruction and metabolic disturbances due to inflammation. IFN, interferon; IL, interleukin; ROS, reactive oxygen species; NO, nitric oxide; VEGF, vascular endothelial growth factor; PDGF, platelet-derived growth factor; COX, cyclooxygenase; MMPs, matrix metalloprotease; TNF, tumor necrosis factor; ARG, arginase; CCR, CC chemokine receptor; CXCR, CXC chemokine receptor; LDL, low-density lipoprotein.

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