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The Complement System in Ovarian Cancer: an Underexplored Old Path

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The Complement System in Ovarian Cancer: an Underexplored Old Path cancers Review The Complement System in Ovarian Cancer: An Underexplored Old Path Yaiza Senent 1,2,3, Daniel Ajona 1,2,3,4,*, Antonio González-Martín 1,5, Ruben Pio 1,2,3,4,† and Beatriz Tavira 1,3,6,† 1 Translational Oncology Group, Program in Solid Tumors, Cima University of Navarra, 31008 Pamplona, Spain; [email protected] (Y.S.); [email protected] (A.G.-M.); [email protected] (R.P.); [email protected] (B.T.) 2 Department of Biochemistry and Genetics, School of Sciences, University of Navarra, 31008 Pamplona, Spain 3 Navarra Institute for Health Research (IdISNA), 31008 Pamplona, Spain 4 Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain 5 Department of Oncology, Clinica Universidad de Navarra, 28027 Madrid, Spain 6 Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, 31008 Pamplona, Spain * Correspondence: [email protected]; Tel.: +34-948-19-47-00 † These authors contributed equally to this work. Simple Summary: Ovarian cancer is one of the leading causes of death among women and the most lethal cause of death from gynecological malignancy in developed countries. The immune system plays an essential role in ovarian cancer progression, and its modulation may be used as an effective therapeutic tool. In this review, we examine the relevance of the cellular and humoral components of the adaptive and innate immune responses in ovarian cancer, focusing on the role of an essential component of innate immunity, the complement system. Elements of this system show Citation: Senent, Y.; Ajona, D.; González-Martín, A.; Pio, R.; Tavira, tumor-promoting activities that impede the efficacy of developing treatment strategies. We discuss B. The Complement System in evidence that suggests a role of complement components in the progression of ovarian cancer and Ovarian Cancer: An Underexplored provide a rationale for evaluating the inhibition of complement components in combination with Old Path. Cancers 2021, 13, 3806. immunotherapies aimed to reactivate antitumor T-cell responses. https://doi.org/10.3390/ cancers13153806 Abstract: Ovarian cancer is one of the most lethal gynecological cancers. Current therapeutic strategies allow temporary control of the disease, but most patients develop resistance to treatment. Academic Editors: Ion Cristóbal and Moreover, although successful in a range of solid tumors, immunotherapy has yielded only modest Marta Rodríguez results in ovarian cancer. Emerging evidence underscores the relevance of the components of innate and adaptive immunity in ovarian cancer progression and response to treatment. Particularly, over Received: 2 July 2021 the last decade, the complement system, a pillar of innate immunity, has emerged as a major regulator Accepted: 26 July 2021 of the tumor microenvironment in cancer immunity. Tumor-associated complement activation Published: 28 July 2021 may support chronic inflammation, promote an immunosuppressive microenvironment, induce Publisher’s Note: MDPI stays neutral angiogenesis, and activate cancer-related signaling pathways. Recent insights suggest an important with regard to jurisdictional claims in role of complement effectors, such as C1q or anaphylatoxins C3a and C5a, and their receptors published maps and institutional affil- C3aR and C5aR1 in ovarian cancer progression. Nevertheless, the implication of these factors in iations. different clinical contexts is still poorly understood. Detailed knowledge of the interplay between ovarian cancer cells and complement is required to develop new immunotherapy combinations and biomarkers. In this context, we discuss the possibility of targeting complement to overcome some of the hurdles encountered in the treatment of ovarian cancer. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. Keywords: ovarian cancer; adaptive immunity; innate immunity; complement system; immunother- This article is an open access article apy; cancer immunology; tumor microenvironment distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Cancers 2021, 13, 3806. https://doi.org/10.3390/cancers13153806 https://www.mdpi.com/journal/cancers Cancers 2021, 13, 3806 2 of 19 1. Current Status of Ovarian Cancer: Clinical Perspective and Needs Ovarian cancer is the most lethal gynecological cancer in developed countries [1]. According to data from the US National Cancer Institute (NIH), the five-year survival rate for ovarian cancer is 49.1% [2]. This can be attributed to a delay in the diagnosis due to the lack of specific symptoms; 70% of cases are diagnosed in stage III or IV, making it difficult to treat with curative intent [3]. Ovarian cancer is a complex disease that com- prises different tumor types, of which epithelial ovarian cancer represents 90–95% of all cases [4]. The current standard treatment includes surgery and platinum-based chemother- apy followed by a maintenance period with the anti-angiogenic therapy bevacizumab [5]. Initial responses to chemotherapy are frequently high, but unfortunately, up to 70% of patients experience recurrence within the first three years, especially patients who are late-diagnosed [5]. Survival rates have recently improved with the introduction of a new generation of poly (ADP-ribose) polymerase inhibitors (PARP inhibitors (PARPi)). These drugs, administered after chemotherapy, prolong the time during which the disease does not progress, mainly in patients carrying BRCA mutations [6]. Despite this great advance, the overall survival of patients with ovarian cancer is still low. There are a variety of fac- tors associated with chemoresistance and relapse, including interactions between ovarian cancer cells and their surrounding immune microenvironment [7]. Ovarian cancers are considered “immunogenic tumors” in which spontaneous antitumor immune responses have been demonstrated [8,9]. The presence of tumors infiltrating CD8+ lymphocytes in the tumor microenvironment (TME) is associated with longer recurrence-free and overall survival [10,11], whereas the recruitment of regulatory T (Treg) cells is correlated with a poor outcome [12]. These associations indicate that ovarian cancers could respond to im- munotherapy. However, immune checkpoint inhibitors (anti-CTLA-4 or anti-PD-1/PD-L1) have yielded modest clinical results in ovarian cancer patients [13,14]. A better understand- ing of the interplay between ovarian tumor cells and the immunological players in innate and adaptive immunity is critical for developing strategies to overcome the resistance of ovarian cancers to immunotherapy [15,16]. A major effector of innate immunity is the complement system, which represents one of the first lines of defense that distinguish “self” from “non-self” [17]. This system is composed of more than 50 soluble or membrane-bound effectors, regulators, and receptors, and it plays a relevant role in numerous physiological and pathological processes, including cancer [18]. Some evidence suggests that the modulation of complement activation may be exploited for the development of successful treatments against cancer [19,20]. In this review, we discuss the role played by components of adaptive and innate immunity on the development and progression of ovarian cancer. We mainly focus on the complement system, its role in the TME, and the rationale behind the use of complement modulators for the treatment of ovarian cancer. 2. Cellular and Humoral Immune Components of the Ovarian Tumor Microenvironment The continuous feedback between tumor cells and the immune system is now recog- nized as a distinguished cancer hallmark [21]. Neoplastic transformation is characterized by the acquisition of tumor-associated molecular patterns that can be detected by the immune system. It is believed that upon recognition, innate and adaptive immunity can eliminate the vast majority of incipient cancer cells, avoiding tumor formation. However, the immune system is unable to eliminate all emerging malignant cells. When transforming cells escape from immune-mediated elimination, a dynamic interplay is established between tumor cells and the immune system, resulting in tumor-associated immune responses that may facilitate the development and progression of cancer [22]. In the case of ovarian tumors, a plethora of immune and non-immune cell types and non-cellular elements are found in the TME, not only in primary tumors but also in ascites and metastases [23]. The co-existence of multiple distinct tumor immune microenvironments within a single individual highlights the high plasticity and adaptability of ovarian cancers [24]. Herein, we summarize the Cancers 2021, 13, 3806 3 of 19 main roles of the cellular and humoral elements of the immune system in ovarian tumor progression. 2.1. Cellular Immune Components Tumor cells co-exist with non-immune and immune cells, and this relationship de- termines the natural history of the tumor and its resistance or response to therapy. The cellular immune components of the ovarian TME include T and B lymphocytes, natural killer (NK) cells, dendritic cells (DCs), polymorphonuclear cells, and macrophages. T cells are a prominent component of the ovarian TME. Infiltration by CD8+ T cells is indicative of an ongoing immune response and is associated with a favorable prognosis [25]. Upon activation, tumor-specific CD8+ T cells secrete IFN-γ, tumor necrosis factor (TNF)- α, and cytotoxic mediators. However, in the ovarian TME, CD8+ T-cell responses are often
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