Mini Review - (2022) Volume 8, Issue 7
Received: 06-Jul-2022, Manuscript No. IPGOCR-22-14237; Editor assigned: 08-Jul-2022, Pre QC No. IPGOCR-22-14237 (PQ); Reviewed: 20-Jul-2022, QC No. IPGOCR-22-14237 (Q); Revised: 25-Jul-2022, Manuscript No. IPGOCR-22-14237 (R); Published: 01-Aug-2022, DOI: 10.36648/2471-8165.8.7.34
In gynecologic malignancies, the intricate tumor microenvironment is a significant modulator of anti-tumor immune responses. The effectiveness of conventional chemotherapy and cutting-edge immunotherapy techniques is significantly impacted by how cancer cells interact with the wide range of immune effector cells. We pay particular attention to the function of macrophages in ovarian, endometrial, and cervical malignancies in this review. We talk about how macrophages developed and how the stimuli from their microenvironment determine their polarization status. Tumor-associated macrophages (TAMs) within the tumor niche influence treatment outcomes by promoting tumor development and mediating immune-suppression. We describe clinical tactics that specifically target TAMs, such as blocking immunological checkpoints, preventing monocyte recruitment to the tumor, enhancing phagocytosis, and inhibiting macrophage differentiation.
Gynecologic malignancies; Ovarian tumor; Gynecological cancer
Recent developments in our comprehension of how the immune system and cancer interact have produced intriguing new therapy modalities. Instead than focusing on the functions or signaling pathways inside the cancer cell, immunotherapy strengthens the immune system's capacity to identify and eliminate cancer cells. The complex microenvironment in gynecologic malignancies, which includes a wide range of immune effector cells, controls the response to anti-neoplastic therapy, including immunotherapies. Deeper understanding of the numerous elements of this microenvironment and their interactions has resulted in the creation of cutting-edge therapeutic approaches with significant promise for enhancing the prognosis of patients with gynecologic malignancies.
From the development of the original tumor through the spread of metastatic disease, inflammation is a key factor in various stages of carcinogenesis. The development of an environment that is immunosuppressive and hinders the immune system from attacking the tumor effectively is a crucial event in the course of tumor growth. Both the innate and adaptive immune systems are impacted by the tumor microenvironment's several levels of immunosuppression, including T cell fatigue and inadequate dendritic cell antigen presentation.
Myeloid derived suppressor cells (MDSCs), which regulate immune suppression to promote tumor development and metastasis, have a wide landscape in the tumor microenvironment [1]. They are split into two primary subsets, polymerphonuclear MDSCs (pMN-MDSCs) and monocytes MDSCs, based on their various morphological and behavioral traits (m-MDSCs). By controlling the expression of a number of cell-surface markers, m-MDSCs specialize and grow into tumor-associated macrophages (TAMs) in the tumor microenvironment. TAMs perform a number of different tasks, some of which are immunological responses such the phagocytosis of cancer cells and immunosuppression. TAMs secrete a number of substances that promote tumor growth, such as VEGF for angiogenesis.
Macrophages that live in tissue
The yolk sac of an embryo serves as the source of tissueresident macrophages, which can sustain themselves and have a lengthy lifespan. Recent studies on ontogeny and developmental mapping have revealed a crucial and unique function for tissue-resident macrophages. The phenotype and function of tissue-resident macrophages vary depending on the tissue. These macrophages are crucial in the control of metabolism and the mediating of immune inflammatory responses [2]. The Kupffer cells in the liver, the brain microglia, the lung alveolar macrophages, and bone osteoclasts all have similar roles but are also very well adapted to their respective organ-specific functions.
Local cues that trigger a particular transcriptional programme, such as tissue-derived cytokines or metabolites, help to preserve each tissue-resident macrophage phenotype. Colony Stimulating Factor 1 (CSF-1), which is necessary for macrophage survival and proliferation, is one of the most crucial elements. By activating the transcription factor GATA6, which triggers peritoneal-specific localization, polarisation, and control of gut IgA synthesis by peritoneal B-1 cells, peritoneal macrophages in mice respond to omentum-derived Retinoic Acid (RA). The omentum is an early and preferred site of ovarian cancer metastasis, serving as a source of retinoic acid to maintain the peritoneal macrophage tissue resident phenotype. Leukocytes collect in the perivascular region of the omentum to create immunological clusters, commonly referred to as "milky patches." Monocytes' presence in milky areas and early postnatal mice's proliferation of them support the theory that omental macrophages are descended from embryonic omental precursor cells. The concept of local macrophage differentiation is supported by the production of macrophage colony stimulating factor (CSF-1) by cells in the milky spots and the repopulation of macrophages following depletion.
Swarming macrophages
Infiltrating macrophages are bone marrow-derived, in contrast to tissue-resident macrophages. They are frequently replenished by circulating monocytes because of their short lifespan. Growth factors and specific chemokine’s, such as CCL2 and CCL5, attract monocytes from blood arteries into different tissues [3]. Infiltrating macrophages can sense cues in the local environment and differentiate into specialized macrophage populations to support tissue homeostasis, immunology, and inflammation, just like tissue-resident macrophages can.
Tissue environment with macrophages: Macrophages have a highly malleable immunological phenotype that is influenced by cues from the local tissue environment. To become "classically activated" or M1 macrophages, macrophages must be exposed to bacterial lipopolysaccharides (LPS) and/or inflammatory cytokines generated by Th1 cells, such as Tumor Necrosis Factor (TNF) and Interferon (IFN-). Interferon-regulatory factor/signal transducer and activator of transcription (IRF/STAT) family members (IRF3, IRF5, STAT1, and STAT5), Nuclear Factor B (NFB) heterodimer (p50–p65), and hypoxia-inducible factor one all work together to activate a cascade of transcription factors that results in the M1 phenotype (HIF1).
As a result, whereas the traditional M1 or M2 description of macrophage polarisation state is useful for defining extreme situations, it does not adequately describe the dynamics of macrophage function as a whole. Additionally, despite the advancements, our capacity to foresee the biological effects of targeting a particular macrophage subtype is still constrained by the intricacy of macrophage activation states in vivo. The definition of these macrophages in the context of health and disease utilising next-generation sequencing will be extremely beneficial.
Macrophages and prognosis: Numerous researches have evaluated the function of tumor-associated macrophages as a prognostic indicator in gynecologic malignancies. Several histology markers, including CD68, a pan-macrophage marker, HLA-DR+ and iNOS+ for M1 macrophages, and CD163 or CD206 for the M2-macrophage population, have been used to examine the presence of macrophages in tumor tissue. As demonstrated for breast, gastric, endometrial, cervical, and ovarian cancers as well as other cancers, the presence of M2-macrophages is typically linked to a poor prognosis [4].
TAMs and ovarian epithelial cancer: Numerous investigations have shown that TAMs play a significant tumor-promoting function in epithelial ovarian cancer. In a study on epithelial ovarian cancer, a high density of CD163+ M2 TAMs was associated with an advanced stage and a bad prognosis for the patient. Important information on the effect of TAMs on immunological checkpoints such B7-H4 and PD-1/PD-L1 in ovarian cancer has been provided by other investigations. These immunological checkpoints regulate the length and intensity of an immune response and act as inhibitory mechanisms to keep the immune system in a self-tolerant condition. By expressing B7-H4 and PD-L1, cancer cells can use immune checkpoint pathways to their advantage and avoid immune monitoring. A trans membrane protein called B7-H4 has an unidentified ligand on T cells. The ligand for PD-1 on T cells, PD-L1, inhibits cytotoxic T cell responses and promotes T cell exhaustion. It's interesting to note that TAMs can express B7-H4 and PD-L1, aggravating an immunosuppressive environment.
Endometrial cancer and TAMs: Similar findings have been made that support TAMs' role in endometrial cancer tumor promotion. Endometrial carcinomas have higher CD68+ macrophage density than normal endometrium in both the epithelial and stromal compartments [5,6]. It's interesting to note that TAMs appear to contribute to the endometrial cancerrelated actions of oestrogen and progesterone. For instance, Jiang et al. demonstrated that a decline in the expression of progesterone receptor was connected with an increase in TAMs in endometrial cancer. It's interesting to note that Ning et al. showed that macrophages can influence how estrogensensitive endometrial cancer cells are, hence promoting the development of estrogen-dependent tumors.
Macrophage phagocytosis
The majority of contemporary immunotherapy techniques have centered on blocking immunological checkpoints on B and T cells, which make up the adaptive immune system. The CD47/SIRP interaction mediates a similar immunological checkpoint in the innate arm. In the 1980s, CD47, an integrinassociated protein, was shown to be a tumor antigen in human ovarian cancer [7]. CD47 is overexpressed on cancer cells. As a "don't eat me signal," CD47 inhibits macrophage-mediated phagocytosis by tying up the Signal-regulatory Protein Alpha (SIRP) that is present on macrophages. Tyrosine phosphatase is activated by downstream signalling, and myosin buildup is inhibited at the phagocytic synapse's submembrane assembly location.
Anti-neoplastic agents and TAMs
According to numerous studies, some anti-neoplastic drugs used to treat ovarian cancer can alter the number and activity of TAMs in the tumor microenvironment [8]. For instance, the agent trabectedin intercalates with the DNA's minor groove and damages the DNA in tumor cells. Trabectedin alters the expression of genes for inflammatory chemokines and angiogenic factors via interacting with DNA-binding proteins.
Within the microenvironment of gynecologic malignancies, TAMs play significant pro- and anti-tumor roles. A significant research challenge in this highly dynamic cell population is to better understand how TAMs affect key pathways of tumor growth, metastasis, and existing anti-neoplastic therapy. It is intriguing to consider TAMs as targets for cutting-edge immunotherapy strategies that have a great deal of promise to significantly improve the lives of people with gynecologic cancers.
The author has no conflicts of interest to declare.
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Citation: Hadhi Z, Qureshi A (2022) Gynecologic Malignancies have Tumor-associated Macrophages: A Mini Review. Gynecol Obstet Case Rep. Vol.8 No.7:34.
Copyright: © Hadhi Z, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
