Blocking CD47-SIRPα Signal Axis as Promising Immunotherapy in Ovarian Cancer.

An Inventory of Epithelial Ovarian Cancer Targets: “Evidence-based” Options-Review Blocking CD47-SIRPα Signal Axis as Promising Immunotherapy in Ovarian Cancer Cancer Control Volume 30: 1–17 © The Author(s) 2023 Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/10732748231159706 journals.sagepub.com/home/ccx Xukai Luo, MM1 , Yini Shen, MM1, Wu Huang, MM1, Yiting Bao, MM1, Jiahang Mo, MM1, Liangqing Yao, MD1, and Lei Yuan, MD1 Abstract Among the three primary gynecological malignancies, ovarian cancer has the lowest incidence but the worst prognosis. Because of the poor prognosis of ovarian cancer patients treated with existing treatments, immunotherapy is emerging as a potentially ideal alternative to surgery, chemotherapy, and targeted therapy. Among immunotherapies, immune checkpoint inhibitors have been the most thoroughly studied, and many drugs have been successfully used in the clinic. CD47, a novel immune checkpoint, provides insights into ovarian cancer immunotherapy. This review highlights the mechanisms of tumor immune evasion via CD47-mediated inhibition of phagocytosis and provides a comprehensive insight into the progress of the relevant targeted agents in ovarian cancer. Keywords ovarian cancer, immunotherapy, CD47, immune checkpoint, immune checkpoint inhibitors Received September 20, 2022. Received revised January 30, 2023. Accepted for publication February 2, 2023. Introduction Ovarian cancer (OC) is one of the deadliest female malignancies, with the lowest incidence but the worst prognosis among all gynecological malignancies. According to clinical guidelines and expert consensus, cytoreductive surgery followed by platinum-based chemotherapy is the standard treatment for most patients with OC.1 Related clinical symptoms are relieved under this standard treatment; however, OC is prone to recurrence and drug resistance, resulting in a five-year survival rate of less than 50%.2 Despite significant progress in surgical techniques and drug therapies, the survival of patients with advanced OC has not improved. Therefore, there is an urgent need to get OC out of therapeutic dilemmas.3 Growing evidence has demonstrated that malignancy is a heterogeneous disease with immunogenicity, and its occurrence, development, and metastasis rely on immune suppression.4 Immunotherapy targeting immunogenicity is a hotspot of anti-tumor therapies and has been successfully used in clinics as a novel anti-tumor option after traditional treatments (e.g., surgery, radiotherapy, chemotherapy, and endocrine therapy).5 Along with the discovery of immune checkpoints (ICs), immune checkpoint inhibitors (ICIs) have become the focus of research in tumor immunotherapy.6–8 ICIs restore self-clearing and monitor the function of the immune system by blocking inhibitory signals. Various ICIs have shown anti-tumor activity in preclinical models, and some have been successfully used in clinics.6–11 Programmed cell death protein-1 (PD-1) and its ligand (PD-L1) inhibitors have been the most successful and widely used ICIs.12 Nevertheless, new ICIs are continuously being identified and developed. The known ICIs primarily act on the adaptive immune system. However, only 10%-30% of patients with OC show long-term and durable responses, followed by acquired 1 Department of Gynecologic Oncology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China Corresponding Author: Lei Yuan, MD, Obstetrics and Gynecology Hospital, Fudan University, 419 Fangxie Road, Huangpu District, Shanghai 200011, China. Email: Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). 2 Cancer Control resistance, which remains a substantial dilemma.7,12–14 CD47 has been identified as the first innate IC, restoring macrophages phagocytosis by blocking the “don’t eat me” signal.15,16 CD47 is a promising therapeutic target to provide insights into new treatment options for patients with OC. show long-term, durable responses, and the remainder mostly do not respond. This result is true in OC.35–37 How to overcome acquired resistance in the development of ICIs is critical, prompting us to explore new targets in tumor immunotherapy to solve this predicament. The Development of ICIs Innate ICs Adaptive ICs The immune system consists of the innate and adaptive immune systems, both of which must be activated simultaneously to obtain sufficient anti-tumor effects.38 CTLA-4 and PD-L1 has garnered considerable attention, which mainly acts on adaptive immunity, but the impact of innate immunity is ignored. In innate immune responses, antigen-presenting cells (APCs) present antigens after phagocytes take up tumorspecific antigens; NK cells directly kill tumor cells, or APCs trigger an adaptive immune response to participate in anti-tumor responses by presenting antigens to T cells.39 Brake-like molecules are also found during the innate immune response. CD47 is the first identified innate IC,40 and Oldenborg described its anti-phagocytic effect by observing the rapid clearance of erythrocytes from CD47 / mice injected into wild-type mice, but macrophage depletion removed this effect.41 Van Buerger found that macrophages rapidly cleared senescent erythrocytes with reduced CD47 expression.42 Notably, CD47 has become a research hotspot since the revelation of its innate IC identity. T cells mediated adaptive immune dominates in anti-tumor reaction.5,14 Both the primary signals produced by the interaction between the major histocompatibility complex and T cells receptor (TCR) and the secondary signals offered by the co-stimulatory molecules are necessary to elicit intact T cell responses.14 Functioning as the assistant of T cell activation and proliferation, co-stimulatory molecules are also essential regulators of humoral immunity and cytokine production.17 However, increasing evidence has shown that some members, such as cytotoxic T-lymphocyte-associated protein4 (CTLA-4), PD-L1, PD-L2, PD-1 homolog, and B7-H3, also provide critical inhibitory secondary signals.18 These inhibitory signals act as a “brake” to protect normal cells from the excessive T cells’ attack by attenuating T cell response.18,19 Conversely, multiple tumors suppress anti-tumor immune responses and evade immune attacks by overexpressing these molecules.7 These brake-like molecules and related inhibitors have been dubbed as ICs and ICIs in cancer immunotherapy because of the satisfactory anti-tumor effects of targeting CTLA4. 14,20,21 Mechanically, the increased anti-tumor effects appear to be the result of the simultaneous enhancement of eff (...truncated)