Complement in Tumourigenesis and the Response to Cancer Therapy

Abstract

In recent years, our knowledge of the complement system beyond innate immunity has progressed significantly. A modern understanding is that the complement system has a multifaceted role in malignancy, impacting carcinogenesis, the acquisition of a metastatic phenotype and response to therapies. The ability of local immune cells to produce and respond to complement components has provided valuable insights into their regulation, and the subsequent remodeling of the tumour microenvironment. These novel discoveries have advanced our understanding of the immunosuppressive mechanisms supporting tumour growth and uncovered potential therapeutic targets. This review discusses the current understanding of complement in cancer, outlining both direct and immune cell-mediated roles. The role of complement in response to therapies such as chemotherapy, radiation and immunotherapy is also presented. While complement activities are largely context and cancer type-dependent, it is evident that promising therapeutic avenues have been identified, in particular in combination therapies.

Keywords: cancer; cancer treatment; complement; therapeutic response.

Figure 1

Complement activation pathways. There are three routes by which the complement system can become activated: the classical, the lectin and the alternative pathways. Classical pathway activation is initiated primarily by antigen-antibody immune complexes. C1q of the C1 complex (C1q, C1r and C1s) interacts with the fragment crystallistion (Fc) portion of antigen-bound immunoglobulins, activating C1r, which subsequently cleaves and activates C1s. Activated C1s cleaves C4 into C4a and C4b, and C2 into C2a and C2b leading to assembly of C4bC2a, the C3 convertase. Carbohydrate-based pathogen-associated molecular patterns (PAMPs) trigger activation of the lectin pathway. Mannose-binding lectin (MBL), ficolins or collectins recognise PAMPs, activating MBL-associated serine proteases (MASPs). Similar to the classical pathway, C4 and C2 are cleaved to generate C4bC2a. The classical and lectin complement activation pathways converge at this point to cleave C3 into the potent anaphylatoxin C3a, and C3b, which joins the C3 convertase to form C4bC2aC3b, the C5 convertase. Cleavage of C5 yields the C5a anaphylatoxin and C5b, which polymerises with C6, C7, C8 and C9 to form the membrane-attack complex (MAC). This inserts into target cell membranes to induce lysis. Spontaneous hydrolysis of C3 into C3H₂O occurs in the alternative pathway. Cleavage of factor B (FB) by factor D yields Bb, which associates with C3H₂O to form a C3 convertase. Cleavage of C3 and FB produces C3b and Bb, respectively. The binding of properdin to microbial surfaces recruits C3b, facilitating the assembly of the C3 convertase (C3bBb), and initiating pathway activation. Subsequent cleavage of C3 produces C3b, which combines with the C3 convertase to form a C5 convertase (C3bBbC3b). From this point, the terminal pathway is initiated to assemble the MAC, similarly to the classical and lectin pathways. Complement activation is regulated at various stages of the pathways by several membrane-bound complement regulatory proteins (Complement receptor 1 (CR1), CD46, CD55 and CD59) and circulating factors (C1-inhibitor (C1-INH), factor H (FH), factor I (FI), C4-binding protein (C4BP), clusterin and vitronectin), which are depicted in red, and properdin, which stabilises the alternative pathway C3 convertase.

Figure 2

The influence of complement on response to treatment within the tumour microenvironment. The current understanding of the roles for complement in the response to radiotherapy, chemotherapy and monoclonal antibody-based immunotherapies are depicted. Green arrows illustrate events where complement component(s) have been demonstrated to activate an immune cell or signalling pathway, while inhibitory effects are shown in red. Black arrows indicate the observed influence of complement activities on the therapeutic efficacies of the designated chemotherapy, radiotherapy or immunotherapy treatment, in specified cancer types.