​The Complement System - pathways & function in the immune system

Gone are the days when the complement system was considered solely a companion of its impressive adaptive immune system counterpart. Research in recent decades has demonstrated that complement cascade components play intricate roles in processes spanning from traditional innate defence to angiogenesis, bone metabolism and neural development. These ultimately homeostatic activities demonstrate that the complement system as a whole adopts a key role in immune surveillance (Ricklin et al., 2010; Reis et al., 2018).

What was once thought to be a single protein responsible for enhancing antibody-mediated lysis of target cells is now recognized as a diverse system. Our understanding of complement has progressed from the single protein described by Jules Bordet in 1901 (Bordet and Gengou, 1901), to a family of many soluble and membrane bound effector molecules (Nesargikar, Spiller and Chavez, 2012). Approximately 50 complement components comprise a network of three complement activation pathways, the classical pathway, the mannose-binding lectin (MBL) or lectin pathway and the alternative pathway (Ricklin et al., 2010).

Primarily, the complement system functions as a first line of defence against foreign pathogens (Mark J. Walport, 2001). Activation of the classical complement pathway occurs when antigen-antibody complexes bind to C1q, a subcomponent of the C1 complement protein (Mark J Walport, 2001). Alternative pathway activation can be initiated by polysaccharides and yeast of bacterial origin while the lectin pathway is activated by bacterial or viral carbohydrate-based pathogen-associated molecular patterns (PAMPs) (Merle et al., 2015). Alternative pathway activation also occurs via a process known as ‘tick-over’, during which C3 undergoes spontaneous hydrolysis (Bexborn et al., 2008).

Despite differing methods of initiation, a common element of complement activation pathways are enzymatic convertase complexes, as illustrated in Figure 1. Each pathway contains two convertases responsible for the cleavage of C3 and C5 molecules, proteins central to the complement cascade. C3 and C5 convertases produce the potent C3a and C5a anaphylatoxins, respectively (Merle et al., 2015). The C5 convertase marks the start of the terminal pathway (TP). At this point, all three complement activation pathways converge initiating the terminal phase of the complement cascade. Ultimately, the TP concludes with the assembly of a membrane attack complex (MAC) which results in lysis of the target cell (Muller-Eberhard, 1985). This MAC-mediated cell lysis is a major mechanism by which complement contributes to overall immune surveillance.

A number of soluble and membrane-bound complement regulatory proteins (mCRPs) includingCD46, CD55 and CD59 exist within the complement system to inhibit complement activation (Schmidt, Lambris and Ricklin, 2016). This negative regulation is essential for maintaining homeostasis and allows for control at various points of the complement cascade (Merle et al., 2015).

Figure 1: The complement system. An overview of complement activation pathways illustrating the key molecules involved in each pathway, including the C3 and C5 convertases, and termination of the cascade with the assembly of a membrane attack complex.

Complement system components take part in numerous physiologic activities, as outlined in Figure 2. In addition to MAC-mediated cell lysis, the complement system furthers functions in host defence through opsonisation of target cells by C3 fragments such as C3d (Ricklin et al., 2010). The innate immune response is further enhanced by C5a, which not only acts as a chemoattractant of phagocytic cells, but induces upregulation of activating Fcg receptors on their surface (Klos et al., 2009; Karsten and Köhl, 2012).

Several broadly reviewed roles for the complement system in adaptive immunity have also been discovered (Carroll and Isenman, 2012). Firstly, complement bridges the innate and adaptive immune systems through its significant involvement in antibody production (Pepys, 1972, 1974), with a C3d acting as a molecular adjuvant (Dempsey et al., 1996). In addition, engagement of complement receptor 1 CD21) expressed on B cells and follicular dendritic cells with C3d-opsonised antigen enhances the B cell response. CD21 expressed on B cells associates with CD19 and CD81 to form a coreceptor complex (Matsumoto et al., 1991). Coligation of CD21-CD19-CD81 and the B cell receptor (BCR) with C3d-opsonised antigen results in augmented signalling through the BCR. This signal promotes B cell immunity by lowering the threshold for B cell activation (Carter and Fearon, 1992; Fang et al., 1998; Cherukuri, Cheng and Pierce, 2001). Finally, the complement system also contributes to homeostasis by the elimination of waste through clearance of apoptotic cells (Flierman and Daha, 2007; Trouw, Blom and Gasque, 2008), immune complexes (Schifferli, Ng and Peters, 1986) and synapses (Stevens et al., 2007).

Figure 2: Complement system activities in immunity and homeostasis. The complement system plays essential roles in adaptive immunity and the clearance of waste products in addition to functioning in host defence. Here, the major activities in which specific complement system components, including complement receptor 1 (CR1) and complement receptor 2 (CR2) take part in, are outlined.

Interactions between the host immune system and cancer are complicated, with the immune system playing a dual role of cancer prevention and promotion (Schreiber, Old and Smyth, 2011). Certainly, the complement system is no exception to this and it shares an intricate relationship with neoplastic diseases (Reis et al., 2018).

Research investigating the role of complement in a cancer setting has conventionally focused on complement as an identifier and eliminator of neoplastic cells. Several studies have provided evidence for local activation of complement, supporting the idea that complement is capable of recognizing tumours (Pio, Corrales and Lambris, 2014). These include reports of the deposition of complement components in tumour tissue (Bu et al., 2007) and elevated levels of complement proteins such as C5a in the serum of cancer patients (Corrales et al., 2012). However, cancer cells express a number of mCRPs to regulate complement activation, with many tumours expressing higher levels of mCRPs than normal tissue. As a result, it appears cancer cells are capable of limiting complement activation allowing them to escape from complement-mediated lysis (Fishelson et al., 2003).

Inflammation is now considered a hallmark of cancer, affecting all stages of cancer development from initiation to metastasis (Hanahan and Weinberg, 2011). Therefore it is no surprise that several studies have provided evidence for a pro-oncogenic role for complement in a number of human cancers (Markiewski et al., 2008; Elvington et al., 2014; Lynam-Lennon et al., 2016; Medler et al., 2018). In 2008 Markiewski et al. demonstrated a tumour-promoting role for complement for the first time. Using a TC-1 syngeneic mouse model, they demonstrated that tumour growth was significantly reduced in C3-deficient mice and C4-deficient mice in comparison with control mice. Furthermore, use of a C5a receptor (C5aR) antagonist impaired the growth of tumours when compared to control mice. Similarly, in mice deficient for the C5aR tumour growth was impaired. In both C5aR-deficient mice and those treated with a C5aR antagonist, the retardation of tumour growth observed was comparable to the effects of treatment with paclitaxel (Taxol), a broadly used cancer drug (Markiewski et al., 2008). These results suggested that complement system components take part in tumour-promoting processes.

Since then, potential oncogenic roles for complement proteins contributing to every hallmark associated with carcinogenesis have been described (Rutkowski et al., 2010). These include promotion of angiogenesis, cellular invasion and the production of growth factors (Figure 3). The C5aR for example has been implicated in elevated invasiveness of hepatocellular carcinoma and gastric cancer cells (Hu et al., 2016; Kaida et al., 2016). Recently, the contribution of complement effectors to metastasis has also been extensively reviewed (Kochanek et al., 2018; Ajona et al., 2019). Observation of the roles played by complement-cascade produced anaphylatoxins highlights that complement activation, which in theory should be tumour-inhibiting, can eventually lead to tumour promotion. This is in line with our current understanding that chronic inflammation is tumour promoting (Mantovani et al., 2008).

Figure 3: Tumour-promoting activities of complement cascade components. This figure was in part created using Servier Medical Art templates.

We now appreciate that aside from clear involvement in controlling tumourgenesis, the immune system can affect response to chemotherapy and radiation therapy (radiotherapy) (Apetoh et al., 2007; Gupta et al., 2012). In this respect, it is important that we elucidate the relationship between complement cascade components and the response to cancer therapy.

A large proportion of multimodal therapeutic approaches for the treatment of human cancers include radiotherapy. Unfortunately, response rates to radiotherapy are varied. For instance, neoadjuvant chemotherapy and radiotherapy (neo-CRT) prior to surgery is the current standard of care of patients with locally advanced rectal cancer (Petrelli et al., 2016). Evidence suggests that rectal tumour response to neo-CRT is a predictor of outcome, with the attainment of a complete pathological response (pCR) associated with reduced recurrence rates and improved patient survival. Despite this, just 15-27% of rectal cancer patients achieve a pCR, leaving the large majority of patients subject to the risk of toxicity and therapy-associated complications, without therapeutic benefit (Janjan et al., 1999; Suárez et al., 2008). Currently there are no clinicopathological parameters available to predict response to neo-CRT. As a result, there is global interest in identifying biomarkers of treatment response.

Investigations seeking to broaden our understanding of complements role in neoplastic development have highlighted complement system components as potential biomarkers of response to radiotherapy. Similar to patients with rectal cancer, neo-CRT is present in treatment regimens for the treatment for patients with oesophageal cancer (Napier, Scheerer and Misra, 2014). A study carried out by Maher et al. analysed the presence of the C3a and C4a anaphylatoxins in the serum of patients with oesophageal cancer (Maher et al., 2011). They identified that levels of C3a and C4a were significantly higher in the pre-treatment sera of patients with a poor response to neo-CRT when compared with those with a good response. This suggested that complement proteins may have potential as minimally-invasive predictors of response to neo-CRT. Furthermore, it suggests that the complement system may be important for the tumour response to neo-CRT. Several years later, Lynam-Lennon et al. investigated tumoural expression of C3 in pre-treatment tumour biopsies from patients with oesophageal adenocarcinoma. They demonstratedfor the first time that C3 expression was significantly elevated in biopsies from subsequent poor responders to neo-CRT (Lynam-Lennon et al., 2016).

Aberrant expression of complement cascade components has been correlated with poor clinical prognosis across many other cancers including ovarian, breast and cervical cancer (Cho et al., 2014; Imamura et al., 2016; Maestri et al., 2018). Together, this current understanding suggests that complement may play a role in response to neo-CRT.

The mechanism by which complement potentially affects therapeutic response may be due to interactions within the tumour microenvironment. Although radiotherapy can directly kill cancer cells, we know that effectiveness in part relies on the immune system and CD8⁺ cytotoxic T cells, which are essential anti-tumour cells (Elvington et al., 2014).

A novel role for complement in T cell immunity has been described. Immune cells in addition to tumour cells are capable of producing complement proteins. Local production of C5a and C3a is observed as a result of interactions between T cells and antigen presenting cells. It has been demonstrated that C3a and C5a can regulate the function of T cells (Kwan, Van der Touw and Heeger, 2012). Others have demonstrated that tumour-derived complement can alter tumour infiltration of CD8⁺ cytotoxic T cells. In one study, silencing of the C3 gene in ovarian cancer cells introduced into immune-competent mice was observed to result in a 10-fold increase in the tumour infiltration of CD8⁺ cytotoxic T cells (Cho et al., 2014). Elvington et al. demonstrated that in a murine model of lymphoma, response to radiotherapy was improved following treatment with a complement inhibitor. The addition of complement inhibition to treatment with radiotherapy was seen to enhance the anti-tumour immune response, due to increased tumour infiltration of CD8⁺ cytotoxic T cells and maturation of dendritic cells (Elvington et al., 2014). It is important to note however that in contrast, another study observed that anaphylatoxins produced as a result of radiotherapy-induced complement activation were essential for therapeutic efficacy (Surace et al., 2015).

Another key player in the response to radiotherapy is hypoxia. Hypoxia refers to low oxygen tension arising from the poorly structured vasculature and rapid proliferation rates characteristic of advanced solid tumours. Resistance of hypoxic areas within tumours to radiotherapy is a significant clinical problem as oxygen is essential for therapeutic efficacy (Brown and Giaccia, 1998; Vaupel and Harrison, 2004). In a recent study, mutations in complement system genes were observed to correlate with overall survival in several cancer types. Interestingly, an enrichment of hypoxia gene sets was observed in colorectal cancer patients with complement mutations (Olcina et al., 2018). Colorectal cancer cells were determined to be less sensitive to complement-mediated cytotoxicity when compared with normal colon cells. Hypoxia further increased the resistance of colorectal cancer cells to complement-mediated lysis, as a result of CD55 upregulation. There certainly appears to be a complex interplay between hypoxia and dysregulation of the complement system (Olcina et al., 2019). As hypoxia is often to blame for poor therapeutic efficacy of radiotherapy, further research focusing on the role played by the complement system in this context may shine some light on potential therapeutic targets.

Clearly there is an unmet need globally to determine the factors influencing tumour response to radiotherapy. Identification of predictive markers of treatment response would not only facilitate improved stratification of patients before commencing treatment but would provide novel therapeutic targets to boost response to therapy in the neoadjuvant setting. A clearer understanding of how complement activation products contribute to tumourigenesis is required to determine the clinical potential of complement proteins as biomarkers of therapeutic response. The observed effects of complement on T cells highlights the need for a greater understanding of how complement system proteins can modulate immune cell phenotypes. Similarly, a greater understanding of the mechanisms by which mCRPs modulate response to cancer therapy is required to fully determine their potential as clinical biomarkers and molecular targets (Geller and Yan, 2019). Over 20 complement-targeting drugs are currently being investigated in clinical trials (Ricklin et al., 2018). The results of these trials will help us to understand the effects of complement regulation at various points in the cascade. Ultimately, further research to determine the interactions of complement components at a microenvironment level is required to confirm if and how the complement system contributes to response to radiotherapy. 

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