Ebru KavaklıA. , Nida Dereli ÇalışkanE., Şehnaz Melisa AcarR.
Introduction
The complement system is an ancient, well-conserved part of the innate immune system. Its main role is to clear invading pathogens and toxic compounds from the circulatory system and remove dead cell remnants. Elements of the complement system are proteins (enzymes) and protein fragments produced by the liver1,2. Complement proteins receive infection signals through microbe-associated molecular patterns (MAMPs) or damage-associated molecular patterns (DAMPs) and transmit these signals to regulatory and effector parts of the immune system3. These proteins enter the circulatory system in inactive forms and need particular enzymes to be activated during complement activation1. Most of the complement proteins are bifunctional, allowing cross-talk between the complement system and other effectors or regulators. Consequently, the complement system plays a role in adaptive immunity, hemostasis, neuroprotection, synaptic pruning, and organ development besides its innate immunity function4. The complement system has been associated with several disorders such as Alzheimer’s disease5, cancer, C3 glomerulonephritis as well as autoimmune diseases6. In the tumor microenvironment (TME), complement components are highly prevalent7. Over the years, research has shown that complement has both an anti-tumor role and a pro-tumor role8-10. This review briefly describes the complement system and discusses the relationship between complement and cancer and possible therapeutic approaches.
The Complement Activation
The Classical pathway
The classical pathway relies on antigen-antibody interactions. This pathway contains antibodies, and complement proteins C1, C2, and C4. The Fc (fragment crystallizable) domain of an antibody interacts with the antigen on the target cell surface. The C1 complex consisting of C1q, C1r, and C1s binds to the Fc domain through the C1q component. This binding leads to C1r autoactivation, then C1r cleaves and activates serine protease C1s. C1s cleaves C4 and C2 complement proteins into C4a, C4b, C2a, and C2b. C4b and C2b proteins combine and form a C3 convertase complex1,4,11.
The Lectin Pathway
In the lectin pathway, complement proteins interact with specific carbohydrates such as mannose that are present on the cell surface of pathogens but not on the host cell. This pathway contains Mannose-binding lectin (MBL), MBL-associated serine protease 2 (MASP2), and complement proteins C4 and C2. MBL interacts with the mannose on the cell surface of the pathogen, then MASP2 binds to MBL, creating a complex that resembles the C1 complex. MBL-MASP2 complex splits C4 and C2 into C4a, C4b, C2a, and C2b as in the classical pathway, and the C3 convertase is formed4,11.
The Alternative Pathway
The alternative pathway has a distinct C3 convertase complex than two other activation pathways11,12. Hydrolyzed C3 (C3H2O) in plasma binds factor B, followed by cleavage of factor B by factor D and C3H2OBb complex formation. This complex cleaves C3 into C3a and C3b, and highly active C3b attaches to the target cell surface. C3 on the cell surface recruits Bb and forms an alternative C3 convertase complex12. Once complement activation occurs by any of the activation pathways, the complement system reacts to pathogens and toxic compounds by tagging pathogens with opsonins to facilitate phagocytosis, pro-inflammatory reactions, and recruitment of immune response cells by anaphylatoxins, and forming a membrane attack complex (MAC) on the target cell membrane to kill pathogens11. Figure 1 shows the overview of three complement activation pathways13.
Figure 1. Overview of three complement activation pathways13. In response to antigen-antibody complexes, the C1 complex (C1qrs) leads to the formation of C3 convertase (C4b2a). The lectin pathway has similar downstream events with the classical pathway, except C3 convertase is formed by interaction of mannose residues with MBL (mannose binding lectins) and with the help of MASP (mannose-associated serine proteases). AP self-activates through the conversion of serum C3 to serum C3(H2O). Factor B is cleaved to Bb by factor D and attaches to C3b to generate the alternative pathway C3 convertase (C3bBb).
Anaphylatoxins: C3a and C5a
Anaphylatoxins are protein fragments that take part in the inflammatory response in many ways such as increasing vascular permeability by stimulating the histamine release, serving as chemotactic agents for leukocytes, and enhancing the production of inflammatory mediators like tumor necrosis factor (TNF-), interleukin-1 (IL-1), or interleukin-6 (IL-6)14. C3a and C5a are robust anaphylatoxins whose generations are enhanced by the C3 convertase complex after complement activation. C3 convertase complex cleaves C3 protein into C3a and C3b fragments. It also takes part in the formation of the C5 convertase complex that splits the C5 protein into C5a and C5b4,14. Pro-inflammatory functions of C3a and C5a rely on protein-receptor interactions. C3a receptor (C3aR) and C5a receptor 1 (C5aR1) are G-protein coupled receptors (GPCRs) with seven transmembrane domains and are expressed in many cell types including myeloid innate immune cells. Interaction between the anaphylatoxins and the receptors promotes calcium (Ca2+) influx in the cells that results in the activation of mitogen-activated protein kinase (MAPK) and protein kinase B (PKB/AKT) signaling pathways14. It has been revealed that complement receptors and toll-like receptors (TLRs) are activated simultaneously by MAMPs andDAMPs during microbial infection. Coactivation of complement receptors and TLRs causes an increased activation of MAPKs and transcription factors nuclear factor kappa B (NF-κB) and activator protein-1 (AP-1) that enhances the expression of proinflammatory cytokines and costimulatory molecules3.
Leukocyte Recruitment
C5a participates in the leukocyte recruitment to the inflammatory site by facilitating the passage of leukocytes through the endothelial barrier. During an inflammatory response, leukocytes move over the activated endothelium by weak interactions of selectins and glycoproteins. C5a and other chemoattractants interact with the leukocyte GPCRs that initiate intracellular signal transduction to the integrins15. Integrins are found in three conformational states that determine the activity of integrins. Bent–closed integrins are inactive, and extended–closed integrins are active with low affinity to ligands. When the integrin changes its state to extended–open, it become active with high affinity to ligands16. Activation of integrins leads to a conformational change and increases integrin affinity for the integrin ligands, members of Immunoglobulin (Ig) superfamily adhesion molecules15. The subsequent steps of the leukocyte recruitment, including leukocyte slow rolling, firm adhesion, and strengthening after adhesion occurs as a result of activated integrins’ recognition of their ligands17. These steps are followed by the passage of leukocytes through the endothelial barrier. After leukocyte passage, the chemoattractant gradient directs leukocyte emigration toward the inflammatory site (Figure 2)15.
Figure 2. Role of C5a in the leukocyte recruitment to the inflammatory site15. C5a stimulates a conformational change in integrin molecules of circulating leukocytes. Activated integrins bind strongly to integrin ligands on the epithelium, resulting in the passage of leukocytes through the endothelial barrier.
Opsonins
Opsonins are part of the complement system that marks the pathogens to undergo phagocytosis9,14. Complement-derived opsonins include several key components, including C1q, MBL, and C3-derived fragments such as C3b, iC3b, and C3db. C3b and its derivative fragments coat the pathogen surface by making chemical bonds with amino or carbohydrate groups on pathogens, called opsonization. Opsonins on the pathogen surface interact with complement receptors on phagocytes to initiate phagocytosis3. C3b, a potent opsonin, is generated via cleavage of C3 protein by the C3 convertase complex after the complement activation4. It interacts with the complement receptor 1 (CR1) and the complement receptor of the immunoglobulin superfamily (CRIg)37. CR1 is abundant in phagocytes, and its interaction with the ligand leads to the activation of phospholipase D (PLD) that relays the signal for phagocytosis of opsonized pathogens in neutrophils38. CRIg is the complement receptor that is present on the surface of the tissue-resident macrophages, especially Kupffer cells, which are the tissue-resident macrophages of the liver. C3b and iC3b are the main ligands of CRIg39.
CRIgs interact with opsonins on viral particles, and these particles are phagocytosed by Kupffer cells. After the internalization, CRIgs are transferred to recycling endosomes to return to the cell membrane for further phagocytosis39. C1q and MBL are soluble molecules that play a role in complement activation. In addition, they can function as opsonins. They can mediate the phagocytosis of pathogens by interacting with the related receptors on phagocytes or facilitating the accumulation of C3 and C4 fragments on the pathogen surface via complement activation37.
Membrane Attack Complex (MAC) Formation
Aside from opsonizing target cells, C3b binds to the C3 convertase complex to form a C5 convertase that cleaves C5 into C5a and C5b. The assembly of proteins C5b, C6, C7, and many C9 creates MAC inserted into the cell membrane of the target cell18. MAC forms pores on the target cell membrane and breaks the ion balance by allowing extra Ca2+ influx and potassium (K+) efflux. Increased concentration of intracellular Ca2+ leads to activation of prolytic factors and necrotic cell death. On the other hand, K+ efflux followed by ATP entry generates a signal for the formation of the NOD-like receptor family pyrin domain containing 3 (NLRP3), resulting in the secretion of inflammatory cytokines interleukin-1 beta (IL-1 beta) and interleukin-18 (IL-18)19. As discussed in the review article40, MAC formation induces the activation of the non-canonical nuclear factor-κB (NF-κB) pathway via forming a signaling complex on RAB5+ endosomes. The signaling complex facilitates the stabilization of NF-κB-inducing kinase (NIK), followed by the translocation of NF- κB to the nucleus.
The Complement System in The Tumor Microenvironment (TME)
The complement system is a mediator and regulator of the immune response to fight tumor progression via cytotoxic actions such as targeting antibody-coated cancer cells and promoting local inflammation8. For this reason, the complement system supports antibody-based immunotherapy and facilitates novel treatment options. On the other hand, research carried out in the past years showed that complement elements also participate in tumor promotion. Activation and interaction of complement elements in the TME promote malignant processes of tumors such as tumor cell adherence, tumor-mediated angiogenesis, invasion, and metastasis9,10. Elevated concentrations of complement proteins have been found in tumor experiments with mice and cancer patients. It seems that complement production is upregulated in the tumor microenvironment by endothelial and immune cells that form an integral part of the tumor microenvironment and premetastatic niche7. Recent studies showed that complement activation does not only occur in a convertase-dependent manner in extracellular space but also can occur intracellularly by cleavage of C3 and C5 proteins by extrinsic proteases like cathepsin L, renin, thrombin, and plasmin20. This non-canonical activation of complement proteins has been detected in many cell types including immune cells and tumor cells8,20. One of the recent studies indicated that intracellularly activated C3a in tumor cell lines suppresses tumor-associated macrophages via C3a-C3aR interactions in a way that exogenous C3a cannot21.
Tumor Promoter Effects of The Complement
As previously mentioned, unbalanced complement activation affects local immune responses, causing inflammation and decreased anti-tumor effects7,9,10. In some cases, loss of complement regulation results in tumor formation. Complement factor H (CFH) is a regulatory component of the alternative pathway. A recent study has shown that CFH deficiency in murine cells leads to overactivation of the alternative pathway in the liver, which results in chronic inflammation and eventually hepatocellular carcinoma (HCC). The research also indicates a positive correlation between CFH expression in patients with HCC and their survival rate22. The complement components decrease anti-tumor responses by suppressing T cells. Complement controls myeloid-derived suppressor cell (MDSC) development and recruitment to tumor locations, resulting in inhibition of anti-tumor effects of T cells in TME23. Researchers investigated the immune suppression effects of complement in mice with B16 melanoma cell line. Based on the study conducted with C3 deficient mice and wild-type mice, complement decreases the expression of IL-10 by CD8+ tumor-infiltrating lymphocytes (TILs), reducing their anti-tumor effects. It has been revealed that anaphylatoxins C3a and C5a produced by CD8+ TILs interact with C3aR and C5aR on the CD8+ cell surface. These interactions inhibit IL-10 production in an autocrine manner resulting in tumor growth promotion24. Additionally, tumor-derived complement components show increasing effects on tumor invasion in different cancers. MDSCs and tumor-associated macrophages (TAMs) are stimulated by complement through the C5aR1 and C3aR to release angiogenic factors. A review article20 indicates that C3a and C5a anaphylatoxins can directly stimulate the growth of endothelial cells by enhancing the production of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (BFGF). A study in cutaneous squamous cell carcinoma (CSCS) demonstrates high levels of tumor-derived C1s and C1r proteins in CSCS cells. Decreased expression of C1s and C1r via knock-down resulted in reduced tumor growth and vascularization and led to apoptosis of tumor cells. This study indicates tumor-promoting effects of C1s and C1r in CSCS and considers C1s and C1r as biomarkers and potential therapeutic targets25. A recent study on human gastric cancer cell lines showed that high expression of C5aR and stimulation with C5a increased cancer cell motility and invasiveness. C5a-C5aR signal pathway induces conversion of RhoA-GDP to RhoA-GTP in gastric cancer cells, resulting in cytoskeletal rearrangements that enhance cell motility26. Another study shows that cancer cell-derived C3 promotes cancer invasiveness by disrupting the blood-cerebrospinal fluid (CSF) barrier. The choroid plexus is the epithelium that inhibits the passage of unwanted materials into the leptomeningeal area and secretes CSF. Metastatic cells in the CSF stimulate C3aR receptors on the choroid plexus by releasing C3a. C3aR-C3a interaction breaks the blood-CSF barrier, and tumor-promoting molecules such as growth factors and other mitogens can enter the CSF. Therefore, an environment that supports tumor growth is formed in CSF by C3a and receptor interactions27.
Therapeutic Approaches
Using monoclonal antibodies (mAbs) in cancer immunotherapy is a therapeutic approach that gives promising results. The clinical success of mAb-based immunotherapy relies on stopping oncogenic signaling and tumor proliferation and inducing complement-dependent cytotoxicity (CDC)9. Therapeutic antibodies used in immunotherapy promote antibody dependent cell-mediated cytotoxicity through interaction with Fc gamma receptors (FcγRs) of effector cells28. Additionally, tumor cell-bound antibodies bind to the C1 complement complex via their Fc domain, which triggers the activation of the classical complement pathway. Upon recruitment of a series of complement proteins abundant in serum, the MAC is formed, leading to lysis of target cells29. Complement activation results in the accumulation of opsonins on tumor cells that interact with complement receptors (CRs) on phagocytic cells. Activation of CRs via complement proteins leads to complement-dependent cell-mediated cytotoxicity and phagocytosis30 (Figure 3)9.
Figure 3. Complement-dependent cytotoxicity in the antibody-based immunotherapy9. Antibody-targeted tumor cells activate the complement system via the classical pathway. Complement mediates the tumor cell lysis by releasing pro-inflammatory mediators, opsonization with C3b fragments, and forming MAC on the cell membrane. Phagocytosis of the tumor cell occurs when CR3 and/or CR4 receptors on phagocytes interact with the C3b fragments on the tumor cell.
Rituximab (RTX) and Ofatumumab (OFA) are CD20-targeting (cluster of differentiate 20) antibodies used in clinics in antibody-based cancer therapies. Using RTX and OFA on B-cell malignancies and chronic lymphocytic leukemia (CLL) showed opsonization on CD20+ cells and CDC31. Complement also contributes to tumor cell elimination in radiotherapy, along with mAb-based immunotherapy. A recent study showed an increase in the local anaphylatoxin and related receptor production after radiotherapy, indicating radiotherapy stimulates local complement activation. Tumor-associated dendritic cells (DCs) generate high amounts of complement proteins and highly express receptors such as C3aR1 and C5aR1 after radiotherapy resulting in DC maturation and activation of T cells’ effector functions. DC maturation upon radiotherapy also showed an upregulation of γ-interferon production in CD8+ cells32 (Figure 4)33.
Figure 4.The role of the complement in radiotherapy33. Radiation promotes cell necrosis and increases local complement activation. Increased complement activation leads to production of high amounts of C3a and C5a and C3 accumulation on tumor cells. C3a and/or C5a play a crucial role in the activation of dendritic cell maturation and interferon generation by cytotoxic CD8+ T cells.
Since C3aR/C5aR signaling cascades have been associated with tumor growth, promotion, and metastasis, the receptors and the signaling pathways may promise a novel target in cancer treatment. A number of studies showed that inhibiting C3aR/C5aR signaling pathway resulted in decreased tumor growth. Programmed cell death protein-1 (PD-1) regulates the immune system by inhibiting the immune response of T cells. Therefore, anti-PD1/PD1-L (PD-1 Ligand) antibodies that inhibit the PD1 regulatory pathway have been used in cancer treatment. In contrast, not all patients benefit equally from treatment34. One of the recent studies has suggested that anti-PD1 and anti-PD1-L antibody treatment combined with inhibition of C5a signaling by PMX53 (a C5a antagonist) enhanced the efficiency of anti-PD1/PD1-L treatment and resulted in decreased tumor volume in MC38 tumors of mice. In combination therapy using anti-PD1/PD1-L and C5a antagonists, increased levels of CD8+ T cells are responsible for the anti-tumor response35. Another study investigated the effects of down-regulated C3aR and C5aR on HCC cell lines since C3aR and C5aR are highly expressed in HCC cells. The knockdown of C3aR and C5aR by small interfering RNAs si-C3aR and si-C5aR demonstrated tumor suppressor effects, such as decreased cell proliferation and apoptosis36.
Conclusion
The complement system facilitates immune functions of innate immunity and takes part in the removal of pathogens2. The complement system kills the pathogen by opsonization and MAC as well as stimulating immune cells via anaphylatoxins5. It has been shown that complement proteins are present in TME and have double roles in showing cytotoxic effects on tumors and promoting tumor growth11. Today, mAb-based immunotherapy relies on complement-dependent cytotoxicity12. On the other hand, there are many studies indicating complement protein-receptor interactions increase tumor malignancies and invasiveness13. Therefore, further studies need to be conducted to understand the mechanisms and pathways of the complement system in cancer to develop complement-targeted therapies.
Drugs and treatment methods mentioned in the review article are based only on the information obtained from the articles. Please consult a specialist physician for diagnosis, treatment and drug use.
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