Complement in cancer: untangling an intricate relationship

Abstract

In tumour immunology, complement has traditionally been considered as an adjunctive component that enhances the cytolytic effects of antibody-based immunotherapies, such as rituximab. Remarkably, research in the past decade has uncovered novel molecular mechanisms linking imbalanced complement activation in the tumour microenvironment with inflammation and suppression of antitumour immune responses. These findings have prompted new interest in manipulating the complement system for cancer therapy. This Review summarizes our current understanding of complement-mediated effector functions in the tumour microenvironment, focusing on how complement activation can act as a negative or positive regulator of tumorigenesis. It also offers insight into clinical aspects, including the feasibility of using complement biomarkers for cancer diagnosis and the use of complement inhibitors during cancer treatment.

Figure 1. Complement mediates tumour cytolysis in the context of antibody-based immunotherapy

Schematic illustration of the basic humoral and cellular elements that evoke tumour cytolysis in the context of monoclonal antibody (mAb)-based cancer immunotherapy. Direct tumour cell elimination is achieved by (i) complement-dependent cytotoxicity (CDC) and (ii) antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent phagocytosis elicited upon targeting of tumour antigens by clinically available therapeutic mAbs. Tumour-targeted mAbs known to elicit complement-mediated cytolytic responses include the anti-CD20 mAbs rituximab and ofatumumab in B cell lymphomas and chronic lymphocytic leukaemia. Targeting of tumour cells by therapeutic mAbs triggers complement activation via the classical pathway. Binding of C1q to the Fc portion of these antibodies leads to the assembly of the active C1 complex (C1q, C1r and C1s), which acquires proteolytic activity over complement components, initiating the cascade. Complement activation leads to tumour cell opsonization by C3-derived opsonins (C3b, iC3b and C3dg) and the generation of potent pro-inflammatory mediators (C3a and C5a), which in turn recruit and activate immune cells with phagocytic properties (neutrophils and macrophages). Downstream activation of terminal complement components results in the assembly of the pore-forming membrane attack complex (MAC), or C5b–C9, on the tumour cell membrane. The anaphylatoxin C5a is known to upregulate activating Fcγ receptors (FcγRs) on phagocytic cells, priming them for enhanced phagocytosis and increasing the magnitude of the tumour cytolytic response. C3-derived fragments (C3b, iC3b and C3dg) on tumour cells bind to CR3 and/or CR4 complement receptors on phagocytes, thus augmenting the FcγR-dependent phagocytic uptake of opsonized tumour cells.

Figure 2. Complement activation in the tumour microenvironment promotes tumorigenesis

A schematic illustration of the fine interplay between complement effectors, tumour cells and innate and adaptive immune cells in the tumour microenvironment, highlighting the many means by which complement contributes to tumour progression. Complement proteins can be secreted by tumour cells or tumour-infiltrating immune cells or can enter the tumour stroma through the vasculature. Local complement imbalance and complement activation within the tumour vasculature can lead to the release of pro-inflammatory factors by both tumour cells and tumour-infiltrating myeloid cells (for example, macrophages and dendritic cells (DCs)). Deregulated complement activation perpetuates macrophage-sustained tumour inflammation, creating a favourable environment for tumour growth. Local release of distinct complement activation fragments, such as C5a, recruits myeloid-derived suppressor cells (MDSCs) into the solid tumour. MDSCs exert potent immunosuppressive effects by ablating effector CD8⁺ T cell responses and facilitating tumour growth. Complement proteins have also been shown to modulate CD4⁺ T helper cell responses within the tumour microenvironment, shifting the inflammatory milieu towards a pro-tumorigenic phenotype. Complement activation products have been shown to promote tumour-associated angiogenesis, enhancing cell invasion into adjacent tissues and tumour metastasis to distant organs. Moreover, complement activation has been associated with the induction of a neutrophil-driven hypercoagulative state in certain solid tumours that further promotes tumour progression. In this respect, complement activation triggers the accumulation of pro-tumorigenic neutrophils within solid tumours, potentiating their procoagulant responses (for example, NETosis) and thus establishing a link between complement-driven coagulation, inflammation and tumour progression.