Abstract
Simple SummaryOvarian 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 tumor-promoting activities that impede the efficacy of developing treatment strategies. We discuss evidence that suggests a role of complement components in the progression of ovarian cancer and provide a rationale for evaluating the inhibition of complement components in combination with immunotherapies aimed to reactivate antitumor T-cell responses.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. Moreover, although successful in a range of solid tumors, immunotherapy has yielded only modest 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 the last decade, the complement system, a pillar of innate immunity, has emerged as a major regulator of the tumor microenvironment in cancer immunity. Tumor-associated complement activation may support chronic inflammation, promote an immunosuppressive microenvironment, induce angiogenesis, and activate cancer-related signaling pathways. Recent insights suggest an important role of complement effectors, such as C1q or anaphylatoxins C3a and C5a, and their receptors C3aR and C5aR1 in ovarian cancer progression. Nevertheless, the implication of these factors in 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.
Highlights
The continuous feedback between tumor cells and the immune system is recognized as a distinguished cancer hallmark [21]
High densities of tumor-infiltrating dendritic cells (DCs)-LAMP+ mature DCs suggest the establishment of an antitumor immune response, which is associated with a favorable prognosis in ovarian cancer patients [34]
This immune response is often rendered dysfunctional because of a variety of mechanisms, such as the upregulation of B7-H1 [35], the activation of the endoplasmic reticulum stress response factor X-box binding protein 1 (XBP1) [36], the attenuation of the toll-like receptor-mediated DC activation [37], and the activation of the cyclooxygenase 2 (COX2)/prostaglandin E2 (PGE2) axis to redirect the development of DCs toward the formation of myeloid-derived suppressor cells (MDSCs) [38]
Summary
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]. 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]. 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]. 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]. 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
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