Open Access | Review
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The critical role of macrophages in ovarian cancer treatment
* Corresponding author: Mingyi Wang
Mailing address: Department of Obstetrics and Gynecology, General Hospital of Western Theater Command of Chinese People’s
Liberation Army, Chengdu 610083, China.
Email: wangmingyiog@163.com
Received: 31 August 2022 / Revised: 14 September 2022 / Accepted: 21 September 2022 / Published: 30 September 2022
DOI: 10.31491/APT.2022.09.093
Abstract
The occurrence of and poor prognosis associated with ovarian cancer (OC) pose a serious threat to the health of middle-aged and elderly women. Thus, there is an urgent need to understand the pathogenesis of OC and establish effective therapeutic measures. The OC microenvironment is thought to facilitate malignancy, as well as close relationships among several types of cells. Macrophages are known to be present in the OC microenvironment. They are usually the M1 pro-inflammatory or M2 anti-inflammatory subtype and contribute to the microenvironment via secreting cytokines. The poor prognosis associated with OC is closely related to the negative regulation of M2 macrophage polarization, which contributes to the immune escape of tumor cells and maintains the malignant growth and distant metastasis of OC cells. In this review, we have focused on the involvement of macrophages in OC during the aging process and the macrophage-based therapeutic strategies for OC.
Keywords
Ovarian cancer, macrophage polarization, ageing, tumour associated micro-environment
Introduction
Ovarian cancer (OC) is the most lethal type of malignant tumor of the female reproductive system [1]. The
malignant progression of OC is associated with multiple
elements, including gene mutation, ovulation frequency,
an abnormal host immune response, oncogene activation
and silencing of tumor suppressor genes, and interaction
of tumor cells with growth factors and cytokines in the
tumor-associated microenvironment [2, 3]. Patients with
OC have lower progression-free survival (PFS) and overall survival (OS) rates due to the lack of effective methods
for early diagnosis. Cytoreductive surgery (CRS) and
chemotherapy with paclitaxel/platinum are the most common therapeutic treatments; however, 70% of OC patients
are at risk of recurrence and chemotherapy resistance [4].
Among the many cytological mechanisms involved in the
malignant progression of OC, macrophage polarization is
widely considered an important component.
Macrophages are a class of natural immune cells with a
variety of physiological functions [5]. Upon stimulation,
macrophages can be polarized into the M1 and M2 phenotypes. The characteristics of several subtypes of macrophages are displayed in Table 1 [6-20]. The tumor-associated macrophages (TAMs) found in malignant tumor
microenvironments are typically M2 macrophages, and
these regulate tumor growth, migration, and angiogenesis
by producing a large number of cytokines, growth factors,
extracellular matrix remodeling molecules, and other molecules [21]. Previous studies have found that M2 macrophage polarization is closely correlated with the malignant
progression of colon cancer [22], prostate cancer [23], liver cancer [24], thyroid cancer [25], craniocerebral tumors
[26], pancreatic cancer [27], and other tumors. Therefore,
regulating the activity and phenotype conversion of macrophages [28-29] is a potential therapeutic strategy for
OC that could improve the poor prognosis associated with
OC. This review focuses on the role macrophage polarization plays in OC during aging and treatment strategies
based on macrophage modulation.
Table 1
The differences among several subtypes of macrophages.
| Inducers | Cell expression markers | Cytokine and chemokine production | References | |
|---|---|---|---|---|
| M1a M1b |
IFNc, LPS, TNF | Common markers: CD80, CD86, CD68,
MHC-II, IL-1R, TLR-2, TLR-4, iNOS, IL10,
IL-12; M1a subtype without CD206 or MGL-1, M1b subtype with CD206 and MGL-1 |
TNF-α, IL-1β, IL-6, IL-12, IL-23, IL-27, CXCL9, CXCL10, CXCL11, CXCL16, CCL5, Arg-2, iNOS, ROS | [5-10] |
| M2a | IL-4, IL-13 | MR, AMACI, MHCII, ArgI, IL-1Ra, IL-1R II, FIZZ1, Ym1/2 | TGFβ, IL-10, IL-Ra, CCL17, CCL22, CCL18, CCL22, CCL24 | [11-15] |
| M2b | IC, TLR, IL-1R ligands, IL-1β | MR, MHCII, CD86 | IL-1β, IL-6, TNFα, IL-10, IL-12, CCL1 | [9, 13] |
| M2c | IL-10, Glucocorticoids, TGFβ | MR, CD163, TLR-1, TLR-8, ArgI | IL-10, TGFβ, CCL16, CCL18, CXCL13 | [16, 17] |
| M2d | T L R + A 2 R l i g a n d s , adenosine receptor ligands | VEGF, TNFα, IL-12, IL-10 | IL-10, IL-12, VEGF, TNFα | [18, 19] |
| M3 | Arg1, Chi3l3, Ccr2, Cx3cr1, Ccr1, Ccr9; without CD11c or CD206 | [20] |
The role of macrophages in the poor prognosis associated with ovarian cancer (OC)
OC has the highest mortality rate of all the malignant tumors of the female reproductive system. Macrophages play important roles in the OC microenvironment; they affect the host’s ability to defend against microbes, viruses, and parasites, as well as against tumor cells. OC TAMs are generally the M2 phenotype, contributing to the occurrence, development, distant metastasis, and angiogenesis of malignant tumors and hence the poor prognosis associated with OC [30]. It has been demonstrated that large proportions of CD163+ M2 macrophages are present in epithelial OCs and are related to poor prognosis [31]. In addition, a high M1 to M2 macrophage ratio in OC tissue is associated with early diagnosis and long survival of tumor patients [32]; and the reverse has also been shown [33].
Potential mechanisms involving M2 macrophages that facilitate OC progression
M2 macrophages promote the immune escape of tumor cells by releasing immunosuppressive factors in the OC microenvironment. For example, during the progression of a malignant tumor, macrophages that are stimulated with interleukin (IL)-4, IL-10, and IL-13 polarize into the M2 phenotype and secrete IL-4, IL-5, and IL-6, which in turn induce the progression of angiogenesis, immunosuppression, and matrix remodeling [34]. TAMs regulate tumor-cell migration in the microenvironment by modulating the secretion of and interactions between epithelial growth factor (EGF), tumor necrosis factor alpha (TNF-α), and colony stimulating factor-1 (CSF-1) [35]. In the OC microenvironment, TAMs promote cell invasion by enhancing the activity of c-Jun and (Nuclear Factor-kappa B) NF-κB and the upregulation of SR-A [36, 37]. The cytokines and chemokines secreted by OC cells can increase macrophage recruitment and polarization [38]. For example, it has been shown that leukemia inhibitory factor (LIF) and IL-6 secreted by OC cells promote the differentiation of macrophages into the M2 phenotype [39]. In another study, CCL2 released by epithelial OC cells was found to increase the recruitment of macrophages and M2 polarization in the tumor microenvironment through CCL2/ Monocyte Chemotactic Protein 1 (MCP-1) signaling [40]. It has also been shown that TNF-α, CCL22, and Chemokine (C-X-C motif) ligand 12 (CXCL12) secreted by OC cells induce polarization of M0 macrophages (monocyte) into M2 macrophages in the tumor microenvironment [41]. In addition, the expression of the transmembrane protein semaphorin 4D (SEMA4D) was found to be higher in an OC cell line and the cell culture supernatant than in normal human ovarian cells and the cell culture supernatant, and peripheral blood mononuclear cells (PBMCs) were found to tend to differentiate into M2 macrophages when stimulated by recombinant soluble SEMA4D [42]. It is also likely that Cyclooxygenase-2 (COX-2) derived from OC stem cells affects M2 macrophage polarization via activation of the Janus kinase (JAK) and COX-2/ prostaglandin E2 (PGE2) signaling pathways [43-45].
Effects of macrophages on the malignant progression of different forms of OC
Macrophages play different roles in several types of histologically classified OC. TAM infiltration is most common in serous and mucinous OC, and the infiltration of
M2 macrophages predicts a poor prognosis for serous OC
cases [46]. Serous OC accounts for more than 70% of all
epithelial OCs. Ciucci et al. found that patients with lowgrade serous OC had less infiltrating CD68+
macrophages
and M2 CD163+
macrophages in tumor tissues than patients with high-grade serous OC [47]. These results suggest that the differentiation activity of M2 macrophages is
related to the occurrence, development, and metastasis of
different types of histologically classified OC [48].
In women, smoking can activate nicotinic receptors, and
this activation has been shown to polarize macrophages
into the M2 phenotype, thereby increasing the risk of mucinous OC [49]. However, the relationship between smoking, macrophage polarization, and the risk of mucinous OC needs to be further investigated.
Endometrioid carcinoma and clear cell carcinoma of the
ovary are mostly caused by endometriosis [50]. A study
suggested that CDC42+
macrophages may inhibit endometriosis in endometrioid carcinoma and clear cell carcinoma
of the ovary and thus play a role in alleviating malignant
progression [51]. It has also been shown that glypican-3
(GPC3), which is specifically expressed in ovarian clear
cell carcinoma, can inhibit ovarian tumor growth in mice
by enhancing the proportion of M1 macrophages [52].
Furthermore, B7-H4 is expressed on the surface of OC
cells and is associated with the infiltration of T cells and
CD14+
macrophages in ovarian clear cell carcinoma but
not in serous OC and ovarian endometrioid carcinoma
[53].
Despite several studies having shown that M1 macrophages have significant anti-tumor effects, Untack Cho
et al. found that M1 macrophages could promote OC cell
metastasis by activating the NF-κB signaling pathway
[54].
Together, these findings suggest that TAMs play important
roles in the development and progression of OC. Hence,
the effects of macrophages in different polarization states
on the malignant progression of different histological subtypes of OC must be further explored.
Macrophages can affect ovarian function during aging
Immune dysregulation associated with aging affects the
balance between immune cell subtypes and their relevant
functions, resulting in the occurrence and progression of
cancer [55]. Several characteristics of the aging process,
such as non-infectious low-grade chronic inflammation,
contribute considerably to age-related pathological changes [56] and functional decline [57]. It has also been shown
that aging stimulates higher expression of a large number
of innate immune system macromolecules, cytokines, and
multi-protein complexes [58]. In addition to their beneficial roles, IL-1β and IL-18 also contribute to the occurrence and progression of disease during aging [59].
Ovarian aging is a natural process characterized by follicular depletion and a reduction in oocyte quality, which
result in loss of ovarian function, cycle irregularity, and
eventually infertility and menopause [60]. Ovarian aging
can also involve ovarian myocyte inflammation and the
gradual development of OC [61]. In cases of OC-related
inflammation, it is critical to maintain the balance between
the macrophage phenotypes so that it is in favor of protection against OC rather than in favor of malignant progression.
Macrophages have the ability to modulate ovarian function during the aging process due to their roles in follicle
growth regulation, tissue remodeling during ovulation,
and corpus luteum formation and regression [62]. Interestingly, in cases where there is poor progression of OC, the
increased number of macrophages present may indicate
the critical role these immune cells play during the aging
process [63]. Additionally, M2 macrophages are the main
source of inducers in the tumor-associated microenvironment and contribute to the regulation of tumor metastasis, tumor invasion, and other malignant behaviors [62].
Negatively modulating M2 macrophage polarization and
reducing the proportion of macrophages could delay OC
progression.
Therapeutic strategies for OC that involve modulating macrophages during the aging process
The occurrence and development of tumors can trigger a
series of inflammatory reactions that can serve as therapeutic targets. On the one hand, it has been found that
inflammatory microenvironments can promote drug resistance and gene instability in tumor epithelial cells and
affect the infiltration and colonization of immune cells,
such as macrophages [64, 65]. On the other hand, TAMs
act as a ‘bridge’ between the anti-tumor immune response
and tumor cells during the occurrence and development
of malignant tumors. At present, there are four therapeutic
approaches that target TAMs: inhibition of the growth of
TAMs, prevention of the recruitment of macrophages, repolarization of M2-like TAMs into M1 macrophages, and
nanoparticle- and liposome-based delivery of anti-tumor
drugs [66].
Studies have shown that human recombinant antibody
single-chain variable fragments (scFv) can be used to
prevent the binding of mesothelin and macrophages, thus
inhibiting the polarization of M0 macrophages into TAMs
[67]. Several therapeutic drugs that target TAMs are being
investigated or have been used in clinical practice. For example, trabectedin can interfere with the survival of TAMs
[68], and alemtuzumab reduces the number and activity
of TAMs by targeting surface proteins [69]. Nanoparticles
loaded with cisplatin can be endocytosed by TAMs and
thus affect tumor cells and play a role in targeted therapy
[70]. Histidine-rich glycoprotein (HRG) has been found
to regulate the repolarization of M2-like TAMs into M1
macrophages; hence, it could be used to inhibit the proliferation and metastasis of malignant tumors and promote
an anti-tumor immune response [71]. Paclitaxel, an antitumor drug used in the treatment of OC, can regulate the
repolarization of M2 macrophages into M1 macrophages
through the Toll Like Receptor 4 (TLR4)-dependent
pathway, thereby inhibiting tumor growth [72]. Studies
have also indicated that the relationship between macrophage polarization and OC can be affected by cisplatin.
In cisplatin-sensitive tumor cells, macrophages promote
the epithelial-mesenchymal transition (EMT) process and
EMT-related gene expression, while such effects cannot
be found in cisplatin-resistant tumor cells, suggesting that
macrophage polarization plays a significant role in malignant tumor progression [73].
Some plant extracts have been found to inhibit tumor
growth by altering macrophage polarization. For example,
in OC, neferine affects angiogenesis by regulating the polarization of TAMs, thus exerting anti-tumor effects [74].
In other research, deoxyschizandrin extracted from berries
has been found to inhibit the activity of M2 macrophages,
and onionin A has been found to have a cytotoxic effect
on OC cells and restrain the activity of M2 macrophages
[75, 76]. Thus, these findings indicate that targeting macrophage polarization is an effective strategy for inhibiting
the malignant progression of OC.
Discussion and perspective
OC is considered the most malignant gynecological tumor
type because it has atypical clinical symptoms, is difficult
to diagnose early, and gradually develops chemotherapy
resistance during treatment. Also, there is no effective
treatment for high-grade recurrent OC, and aging is a major factor in the occurrence and progression of OC. Therefore, there is an urgent need to understand the molecular
mechanisms involved in the malignant progression of OC
and to develop effective therapeutic drugs.
The tumor microenvironment is a complex network of
cytokines, exosomes secreted by different cells, immune
cells, fibroblasts, and mesenchymal stem cells. To maintain a suitable tumor microenvironment, several cytokines
are released by different types of immune cells during
aging. Hence, the occurrence and development of tumors
are largely affected by the innate and adaptive immune
responses.
A growing number of studies are showing that suppressing and eliminating tumor cells by activating the innate
immune system is an effective tumor treatment strategy.
Macrophages are part of the infiltrating immune cell
population in the tumor microenvironment and are involved in regulating the malignant progression of OC. In
most cases, M1 macrophages have an anti-tumor effect,
while M2-like TAMs support immunosuppression and
tumor immune escape. Among all the infiltrating immune
cells in the tumor microenvironment, TAMs are typically
the most abundant cell type. By initiating fibrosis, TAMs
regulate the tumor microenvironment, thereby inhibiting
immune defense and facilitating angiogenesis. In various
tumor types, the number of M2 macrophages in tumors is
negatively correlated with patient survival and positively
correlated with tumorigenesis. Hence, alteration of the M1
to M2 macrophage ratio is a potential strategy for treating
OC and improving the associated prognosis.
Declarations
Authors’ contributions
YRW and MYW conceived and designed the project. YRW and MYW were major contributors in writing the manuscript. All authors have read and approved the final version of this manuscript.
Availability of data and materials
Not applicable.
Financial support and sponsorship
None.
Conflicts of interest
The authors declare no conflict of interest.
Ethical approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
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