Surgery, Gastroenterology and Oncology

Cancer is a disease with major societal impact with 18.1 million cases reported globally in 2020. About 16% of all oncological disorders are malignant gynaecological tumours, the most common types being cervical, endometrial and ovarian cancer. The classic methods of treating these diseases are surgery, radiotherapy chemotherapy and different combinations of them, and they are directed against the tumor cell itself. This necessitates the searchfor more and more new and effective therapeutic approaches. Advances in genomic and molecular techniques have led to the introduction of personalized treatment tactics targeting oncogenic pathways rather than the tumor cell itself. Immuno-oncology tries to explain the different mechanisms by which cancer tries to escape from the immune response. One such mechanism is the interaction between the CD47 and SIRPa, thus producing an antiphagocytic "don't eat me" signal. The aim of this review is to address the role of CD47 in thetreatment of gynecological neoplasms. In order to understand this role, the interactions involved in CD47 and its relationship with other immunological cells must be analyzed.

INTRODUCTION

Cancer is a disease with major societal impact with 18.1 million cases reported globally in 2020, of which 9.3 million cases were in men and 8.8 million in women (1). About 16% of all oncological disorders are malignant gynaecological tumours (1), the most common types being cervical, endometrial and ovarian cancer. At more than 604,000 new cases and more than 341,000 deaths in 2020, cervical cancer ranks fourth among women's cancers and seventh overall (2). In 2020, endometrial cancer accounted for over 417,000 new cases and over 97,000 deaths, making it the sixth most frequent cancer in women and thefifteenth most common cancer worldwide (3). Ovarian cancer is the 8th most common cancer in women and the 18th most common cancer overall, with more than 313,000 new cases and more than 207,000 deaths in 2020 (4). The classic methods of treating these diseases are surgery, radiotherapy chemo-therapy and different combinations of them, and they are directed against the tumor cell itself (5). This necessitates the search for more and more new and effective therapeutic approaches. Advances in genomic and molecular techniques have led to the introduction of personalized treatment tactics targeting oncogenic pathways rather than the tumor cell itself (5). However, a significant number of patients do not respond toclassical or personalized approaches, and this raisesthe question of what other cellular, local, or systemic characteristics of cancer are not accounted for that may influence cancer progression and limit treatment response (5). Immuno-oncology tries to explain thedifferent mechanisms by which cancer tries to escape from the immune response (6).

One such mechanism is the interaction between the Cluster of Differentiation 47 (CD47) and SIRPα (signal regulatory protein alpha), thus producing an antiphagocytic "don't eat me" signal (7).The transmembrane immunoglobulin CD47, also referred to as integrin-associated protein (IAP), is expressed on the surface of a variety of cells, shielding them from being annihilated by circulating macrophages. When CD47 expression is decreased in aged or diseased cells, macrophages attack those cells (9). Numerous different tumours have demonstrated elevated expression of CD47, which is linked to a bad prognosis (9). As a result, it has been proposed that targeting the CD47 protein may betherapeutically beneficial in some conditions (8).

The aim of this review is to address the role of CD47 in the treatment of gynecological neoplasms. In order to understand this role, the interactions involved in CD47 and its relationship with other immunological cells must be analyzed.

Ligands of CD47

The most researched relationship is that between CD47 and SIRPa. Bidirectional signalling from thiscontact causes different cell-to-cell reactions, including T-cell activation, promotion of cell-cell fusion, andinhibition of phagocytosis (10-12). Due to CD47's strong affinity for thrombospondin-1 (TSP-1), a secreted glycoprotein involved in angiogenesis and vascular development, nitric oxide signalling in vascular cells is inhibited at several levels by the TSP1-CD47 interaction (13).

TSP-1 binding to CD47 influences a number of vital physiological processes, including angiogenesis and inflammation regulation, cell adhesion and migration, and cell proliferation or apoptosis (10). A number of membrane integrins, including avb3, a2b1, and aIIbb3, interact with CD47. Many cellular processes are impacted by CD47/integrin complexes that are produced as a result of these interactions. Number of membrane integrins, including avb3, a2b1, and aIIbb3, interact with CD47. These interactions lead to CD47/integrin complexes, which have an impact on adhesion,spreading, and migration, among other cellular processes (10,14).

CD47 and immune cells

Nearly all immune cells express CD47, albeit the degree of expression varies widely between cell types and pathological states (15). T cell activation and death-inducing mechanisms are among the many cellular processes that are triggered by CD47 signaling (16). Long-lived memory T cell progenitors can live longer when CD47 is expressed on them because it shields them from macrophages (17). Antigen-presenting cells' (APC) and CD4+ T cells' own expression of CD47 can both control the differentiation of these cells. Byspecifically preventing naïve T cells from developing into Th1 effectors that generate IFN-g, lymphotoxin-a (LT-a), and TNF-a, CD47 ligation can hinder the immune system's ability to eradicate cancer (18,19).

While CD47 loss does not change the inhibitory function of Treg cells, it does increase Treg cell development and regulate the homeostasis of activated CD103+ Treg cells (20). FoxP3 expression is upregulated in naïve T cells following anti-CD47/anti-TSP-1 therapy (20).

The predominant macrophage checkpoint, CD47, sends a "don't eat me" signal to macrophages (22). The interaction between CD47 and SIRPα modifies the polarization state of macrophages and controls their activity (23). Professional antigen-presenting cells,dendritic cells (DCs), are capable of stimulating naive T lymphocytes. They also provide TSP, which can autocrinally decrease the synthesis of IL-12 and IFN-g by interacting with CD47 (24,25). The preservation of immunological hemostasis may also be influenced by the interaction between SIRPa on DCs and CD47 expression on T cells (26). Since DCs removal significantly impairs therapeutic efficacy compared to macrophage depletion, DCs are the primary APCs that cross-prime cytotoxic T cells (27).

CD47 blocks the activation of NK cells, and its absence increases their activity and cytotoxicity (28, 29). Anti-CD47 therapy increases the ability of NK cells to destroy tumor cells by enhancing expression of granzyme B and IFN-g (29). CD47 has therapeutic potential as a checkpoint of NK cells in the tumor microenvironment (30).

CD47 has an important role in the trans-endothelial migration of neutrophils and other leukocytes (31,32). CD47 expressed on myeloid DCs is a critical factor in controlling efficient trafficking through lymphatic and endothelial vessels, seeding in secondary lymphoid organs and participating in T-cell priming (27,33).

CD47 and therapeutic options

The use of checkpoint immunotherapy is growing in popularity and is being used to an increasing number of oncological disorders (34,35). However, not all patients are candidates for this type of treatment, therefore there is a constant need to find new immune checkpoint receptors. Since the innate immune system is the body's initial line of defence against cancer cells, innate checkpoints are becoming more and more attention as viable treatment alternatives (14). The CD47-SIRPa axis is just like this.

The following is the action's mechanism:

• Through a caspase-independent mechanism, CD47 ligation triggers tumour cell death (36,37).
• Anti-CD47 causes tumour cells to be phago-cytically taken up by antigen-presenting cells, which then presents the antigen to T cells (38).
• Anti-CD47 abrogates the TSP-1-mediated inhibitory effect against NK cells, but increases their activity and cytotoxicity (29)
• Blockade of CD47 depends on STING (stimulator of interferon genes), which induces a I/II IFN response mediated by dendritic cells and CD8+ T cells (27).
• The CD47/TSP-1 pathway has pleiotropic effects on the immune system and may have therapeutic potential (39,40).

It is currently accepted in the literature that CD47-SIRPa blockade alone is sufficient to induce tumor regression (41), but this may not be entirely sufficient. Additional prophagocytic receptors such as calreticulin, SLAMF7, and macrophage antigen-1 may be involved to enhance the antitumor response (14).

Blockade of CD47-SIRPa as a therapeutic option for the treatment of gynecological neoplasms is still at the experimental level.

Cervical cancer (CC)

In 2019, Li et al experimentally demonstrated that blocking SIRPa in DCs led to increased secretion of cytokines (TNF-a/IL-12/IL-6), IFN-g from T lymphocytes and in vitro/in vivo observed antitumor activity against CC (42). These results suggest that SIRPa silenced DCs vaccination is a potential therapeutic option against cervical cancer.

Other studies are looking at possible ways to increase the effectiveness of blocking the CD47-SIRPa axis. For example, CD47 has been shown to be associated with programmed death ligand 1 (PD-L1; or CD274, B7-H1), which sends the all-important "don't find me" signal to the adaptive immune system (43). It has been shown that CD47 blockade therapy canactivate CD8+ T immune responses to tumors (44), while PD-1 blockade therapy promotes phagocytosis of tumor-associated macrophages (45,46). Xu et al. demonstrated that increased expression of LSD1 (the first discovered histone demethylase) was associated with progression of CRC, and its inhibition increased the therapeutic effect of CD47/PD-L1 blockade therapy in CC (47).

Another study demonstrated that high CD47 expression was associated with increased HIF target gene expression (HIF-1a and HIF-2a are hypoxia-inducible factors) and was associated with worse survival (48). It has been reported that there is high expression of ZEB1 in hypoxic cells of squamous cell carcinoma (49). It has been suggested that a combination regimen using a ZEB1 antagonist with simultaneous blockade of the CD47-SIRPa axis may improve the treatment of most patients with squamous CC (50).

Endometrial cancer (EC)

Yang et al reported that CD47 expression correlated significantly with age, clinical stage, histologic grade, histologic type, menopausal status, and prognosis (51). Expression is increased in the following order in patients with endometrial hyperplasia: simple hyperplasia, complex hyperplasia, and atypical endometrial hyperplasia (51).

Sahin et al reported that CD47 expression levelscorrelated with tumor grade, had no statisticallysignificant relationship with myometrial invasion and lymphovascular invasion, and concluded that anti-CD47 antibody therapy is a possible alternative for patients with high-grade EC (52).

Another study concluded that CD47 blockadetherapy, which can re-educate M2 macrophages by increasing their ability to phagocytose, may be an attractive target for tumor immunotherapy for EC (53).

Ovarian cancer (OC)

There are more reports on the role of CD47 in OC since CD47 was initially identified as a tumor antigen in human ovarian cancer (54).

Al-Sudani et al. examined the antitumor efficacy of anti-CD47 therapy both alone and in combination, and they found that patients with gynaecological tumours who had high CD47 expression had a decreased immune checkpoint inhibitor (ICI) response and atendency towards a lower progression-free survival (PFS) (55). Higher CD47 expression correlated negatively with PDL1 and Cytotoxic T-lymphocyte associatedprotein 4 (CTLA4) expression, as well as cytotoxic T cells and dendritic cells, but positively with TGF-b, BRD4, and CXCR4/CXCL12 expression (55). Based on their results, they concluded that anti-CD47 therapy may helpovercome immunotherapy resistance and improve responses to PARP inhibitors in ovarian cancer (55).

A different group similarly found a correlation between lower overall survival (OS) and progression-free survival (PFS) and increased CD47 expression in ovarian cancer (56). They conclude that CD47 has fresh prospects for immunotherapy in patients with ovarian cancer and can be utilised as a possible predictivebiomarker (56). According to Liu et al., using anti-CD47 therapy to conventional treatment methods canprevent OC from metastasizing and from reoccurring (57). A full response to therapy is linked to lowexpression of CD47 (58). And similar findings are reached by other writers (59-63).

Particularly in CC, the function of CD47 expression in gynaecological tumours has not yet been thoroughly understood. Based on the available information, it is evident that the expression levels are correlated with some clinicopathological data in EC, that they areassociated with prognosis, OS, and PFS, that they are related to the therapeutic response to standardtreatment regimens in OC, and that there may be a therapeutic influence in CC. All of this points to thelikelihood that CD47-SIRPα axis blocking is a noveltherapeutic approach to influence gynaecological tumours, both on its own and in combination with other ICIs. CD47 is a promising prognostic and predictive marker in these tumours.

Author’s contributions

All authors have accepted responsibility for the entire content of this manuscript and approved itssubmission.

Competing interests

Authors state no conflict of interest.

Research funding

This work has been supported by Medical University Pleven, Bulgaria (Expression levels of CD8, CD68, CD47 and PDL-1 in cervical cancer and their role in tumorigenesis No 18/2023).

Data availability

The authors declare that all related data areavailable concerning researchers by the corresponding author’s email.

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