Complement in Cancer. Untanglin an Intricate Relatioship

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  An enormous body of data produced by converging disciplines has provided unprecedented insight into the intricate and dynamic relationship that exists between developing tumours and the host immune system 1–3 . It is widely accepted that neoplastic transformation is a multifactorial process that the immune system can detect through genetic and epigenetic changes that alter the antigenic signatures of tumour cells. Control of tumour growth relies on both innate and adaptive mechanisms of immunosurveillance and is subject to the selective pressure exerted by distinct immuno regulatory pathways in the tumour microenvironment 4–7 . In this regard, cancer treatment has been revolutionized by new immuno modulatory approaches that elicit durable clinical responses in cancer patients by restoring anti-tumour immunity and potentiating standard therapeutic regimens, such as tumour radiotherapy  5,8 .Elements of the innate immune response are inte-gral components of antitumour effector mechanisms 3,9 . In many ways, tumour cells are perceived by the innate immune system as noxious, ‘non-self’ matter that must be disposed of  10 . Therefore, potent antitumour cytotoxic responses are elicited by innate immune cells, followed by elimination of opsonized tumour cells through the concerted action of tumour-directed antibodies and complement 9,11,12 . Complement is a phylogenetically conserved branch of the innate immune response that has traditionally been perceived as a network of proteins that rapidly respond to microbial intruders, triggering the release of inflammatory mediators, phagocytic responses and cell lysis 13   (BOX 1) . Growing evidence has indicated, however, that this versatile innate immune effector system mediates key homeostatic functions in processes ranging from early vertebrate development and tissue morphogenesis to tissue regeneration, cen-tral nervous system synaptic pruning, host–microbiota symbiosis and adaptive immune regulation 14–17 . In the context of cancer immunotherapy, complement can be readily triggered into action by damage-associated molecular patterns (DAMPs) exposed on the surface of tumour cells 3,6 . Although the role of complement as an effector mechanism that potentiates antibody- dependent tumour cytolysis has been long appreciated, clinical challenges, such as the upregulation of a wide spectrum of complement regulatory proteins, remain to be addressed 12,18,19 .Clearly, the role of complement as an effector of tumour cytotoxic responses remains relevant to antibody- mediated immunotherapy, guiding new thera-peutic options. Intriguingly, however, accumu lating evidence from studies published in the past decade has pointed to a fascinating paradigm shift: the real-ization that complement activation within the tumour microenvironment can serve a tumour-promoting role by perpetuating local T cell immuno suppression and chronic inflammation that promotes tumour immune escape, outgrowth and metastasis 20–23 . Diverse complement- derived effectors and downstream sig-nalling partners have been implicated in processes ranging from tumour cell anchorage and proliferation to tumour-associated angiogenesis, matrix remodel-ling, migration, tissue invasiveness and metastasis 6,19 . 1 Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania 19104, Philadelphia, Pennsylvania, USA. 2 National Center for Scientific Research ‘Demokritos’,  Athens 15310, Greece. 3 Department of Pharmaceutical Sciences, University of Basel, Basel 4056, Switzerland. 4 Humanitas Clinical and Research Center and Humanitas University, Rozzano-Milan 20089, Italy.*These authors contributed equally to this work.Correspondence to J.D.L. lambris@upenn.edu doi:10.1038/nri.2017.97Published online 18 Sep 2017 Complement in cancer: untangling an intricate relationship Edimara S. Reis 1 *, Dimitrios C. Mastellos 2 *, Daniel Ricklin 3 , Alberto Mantovani  4  and John D. Lambris 1 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 tumsrcenesis. 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. NATURE REVIEWS |   IMMUNOLOGY ADVANCE ONLINE PUBLICATION |   1 REVIEWS © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.    Properdin Factor BFactor BC3bBbC3(H 2 0)BbC3bBb3bC4b2b3bC4b2bC3(H 2 0)Factor DFactor DC3C2C1q C1rC1sC4C5 C5bMACC5aC6C7C8C9 n C5b–C9C3bBbC3aC3bMBL FicolinsMASPs     A    l   t   e   r   n   a   t    i   v   e   p   a   t    h   w   a   y    L   e   c   t    i   n   p   a   t    h   w   a   y    C    l   a   s   s    i   c   a    l   p   a   t    h   w   a   y  Alternative pathway amplification loop Terminal (lytic)pathwayIntracellularcomplementcircuitryExtrinsic protease pathway ConvertasesUnconventionalroutes of activationC3 ‘tick-over’C3 C3b With new insights being gained from a variety of tumour models, it is becoming clear that the contribution of com-plement to cancer pathophysiology is far more complex than srcinally thought and appears to be largely contex-tual, depending on several factors, such as the cellular srcin of the tumour in question, its inherent capacity to produce autologous complement proteins, the nature of the tumour microenvironment and the magnitude of complement activation.In this Review, we discuss current and emerging aspects of complement’s contribution to cancer elim-ination and progression and suggest therapeutic tar-gets with clinical potential. We also place emphasis on clinical challenges faced in translating these findings to efficacious tumour cytotoxic modalities or combination immunotherapies and interrogate the feasibility of using complement-based biomarkers for cancer diagnosis, tumour staging and prognosis. Complementing cancer immunotherapy There is a growing appreciation that durable clinical responses in patients with cancer are more likely to be achieved when targeted therapies that ablate key onco-genic signalling pathways are combined with approaches that effectively reverse tumour-instigated immuno-suppression and augment antitumour immunity — an example has been the success of immune checkpoint blockade 5,8 . Among the currently explored targeted therapies, monoclonal antibody (mAb)–based cancer immunotherapy has gained considerable traction as a Box 1 |  An overview of the complement system The complement system comprises an extensive network of fluid-phase and membrane-bound glycoproteins, cofactors, receptors and regulatory proteins that engage in innate immune recognition, adaptive cell stimulation and pro-inflammatory effector responses 126 . Being a crucial mediator of tissue immunosurveillance, complement responds rapidly to molecular stress signals through a cascade of sequential proteolytic reactions initiated by the binding of pattern recognition molecules (for example, C1q, mannose-binding lectin (MBL), MBL-associated serine proteases (MASPs),   ficolins and properdin (also known as Factor P)) to distinct structures on damaged cells, biomaterial surfaces or microbial intruders 17 . Whereas three ‘canonical’ pathways of activation have been described to date (that is, the classical, alternative and lectin pathways), mounting evidence indicates that complement can be activated via multiple routes, depending on the initiating triggers and the distinct microenvironment or pathophysiological context 126 . The classical pathway is initiated by binding to circulating or surface-bound immune complexes, while the lectin and alternative pathways are triggered by pathogen- associated molecular patters (PAMPs) or aberrant carbohydrate structures on damaged or necrotic cells. All activation pathways converge at the cleavage of C3, an abundant plasma protein that undergoes elaborate conformational changes upon activation, thereby exposing multiple sites of interaction with diverse immune effectors 127 . Notably, the spontaneous low-level hydrolysis of C3 keeps the alternative pathway in ‘standby’ mode to allow for rapid amplification upon microbial challenge 128 . Complement activation culminates in the assembly of short-lived multiprotein complexes with enzymatic activity termed ‘convertases’. These enzymes are responsible for the proteolytic activation of the central components C3 and C5 and the release of their respective bioactive fragments, C3a and C3b, and C5a and C5b. The rapid amplification of C3b deposition via the alternative pathway is a process known to underlie several clinical disorders associated with genetic or acquired complement dysregulation (for example, C3 glomerulopathy) 17,129 . Cleavage of C5 leads to the release of the potent inflammatory mediator C5a and initiates a sequence of protein–protein interactions that induces assembly of the membrane attack complex (MAC, C5b–C9), a multiprotein ‘pore’ with cell activating and cytolytic properties. Unconventional routes of complement activation include the deployment of proteolytic enzymes of the coagulation and fibrinolytic systems that can efficiently cleave both C3 and C5 into their bioactive fragments 130 . These non-canonical routes of activation, in conjunction with the intracellular complement circuitry 38,131 , define a broader pathophysiological base of triggering cues that can initiate homeostatic or disease-tailored complement responses. REVIEWS 2 |  ADVANCE ONLINE PUBLICATION www.nature.com/nri © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.    MACTherapeutic antibodyTumourantigenTumour cell Pro-inflammatory mediators (C3a, C5a)CR3 and/or CR4Fc   RComplementactivationComplement-dependentcytotoxicityCell lysisComplement-dependent cell-mediated cytotoxicityC1 complex C3b Phagocyticcell  viable therapeutic modality and has shown promising results, particularly in the treatment of certain haemato-logical malignancies, such as B cell lymphomas, multiple myeloma and chronic lymphocytic leukaemia 12,24–27 . How mAbs harness the complement system.   The clini-cal benefit of mAb-based immunotherapies is attributed partially to their ability to evoke complement- dependent cytotoxicity (CDC) that culminates in tumour cell elimination 12,18 . Indeed, complement has long been con-sidered a potent cytolytic ‘payload’ for tumour-specific antibodies, and seminal studies in the early 1970s laid the groundwork for what would later become a preva-lent concept in the field 28,29 . Notably, various cancer immuno therapeutic protocols used today in the clinic rely on the two-pronged capacity of mAbs to halt onco-genic signalling and tumour cell growth and to simulta-neously fix complement on the surface of the targeted tumour cells, thereby eliciting CDC 18,24,25 .Despite modest attempts to harness the cytol-ytic capacity of complement in mAb-based cancer immuno therapy over the years, full realization of its tumoricidal potential came only with the US Food and Drug Administration (FDA) approval of ritux-imab, a chimeric anti-CD20 mAb developed for the treatment of B cell lymphomas 12,24 . A wide array of in vitro  studies using cancer cell lines, primary tumour cells, mouse tumour models and blood profiling of patients with chronic lymphocytic leukaemia after mAb infusion have provided evidence for the auxiliary, tumour-destructive role of complement in the context of anti-CD20 immuno therapy  12 . mAbs targeting sur-face antigens such as CD20, CD38 and CD52 that are highly expressed on B cell- or T cell-derived tumours are among the most well-studied tumour- specific mAbs in terms of their ability to elicit CDC 24,27,30 .The binding of mAbs to tumour antigens triggers the concerted activation of multiple effector pathways that operate in parallel to elicit cytolytic responses. These include CDC elicited via the classical pathway of complement activation and assembly of the membrane attack complex (MAC) (BOX 1) ; antibody-dependent cell-mediated cytotoxicity (ADCC), operating primar-ily through the engagement of Fc receptors on natural killer (NK) cells; and antibody-mediated phagocytosis 12   (FIG. 1) . Depending on the magnitude of the comple-ment response on targeted cells, tumour cell elimina-tion can occur either through MAC assembly and direct cell lysis or via recruitment of macrophages that take up opsonized tumour cells through the recognition of opsonic fragments (for example, C3b, iC3b and C3dg) by complement receptors CR1, CR3, CR4 or CRIg 12   (BOX 2) . Concomitant recognition of the Fc portion of tumour-specific mAbs by Fcγ receptors (FcγRs) on macrophages allows for synergistic clearance of tumour cells via complement CR3- and FcγR-dependent uptake (FIG. 1) . Notably, the release of complement-derived inflammatory mediators, such as C5a (BOX 1) , further potentiates the cytolytic activity of mAbs by promoting the recruitment of phagocytic cells and skewing the rel-ative expression of activating and inhibitory FcγRs on neutrophils and macrophages 31 .It should be noted, however, that a wide array of tumour cells, especially in solid tumours, have evolved diverse mechanisms by which they can limit CDC on their surfaces. Overexpression of membrane-bound com-plement regulatory proteins (that is, CD55 (also known as complement decay-accelerating factor (DAF)), CD46 (also known as membrane cofactor protein (MCP)), and CD59) or sequestering of fluid-phase regulators 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 Fc γ  receptors (Fc γ Rs) 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 Fc γ R-dependent phagocytic uptake of opsonized tumour cells. REVIEWS NATURE REVIEWS |   IMMUNOLOGY ADVANCE ONLINE PUBLICATION |   3 © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.  (for example, Factor H or C4-binding protein (C4BP, also known as C4BPA)) (TABLE 1)  by tumour cells has been shown to prevent CDC by limiting C3 opsonization to lev-els well below the threshold required for terminal pathway activation and MAC assembly  32–34 . In this regard, several strategies have been devised to overcome this impediment in mAb-based immunotherapy (discussed below). Beyond cytotoxicity.   Growing evidence indicates that complement, in addition to providing an adjunctive mechanism for mAb-mediated tumour cytolysis, medi-ates a plethora of immunomodulatory functions that are pertinent to tumour immunosurveillance and anti-tumour immunity  35,36 . Fundamental processes such as tumour antigen processing and presentation by anti-gen-presenting cells (APCs), as well as B cell activation and T helper and effector T cell survival and differentia-tion, appear to be influenced by the intricate crosstalk of complement effector proteins with key cellular pathways that drive B cell and T cell responses 37,38 . Dendritic cells (DCs), for instance, express a wide array of complement proteins and receptors 39 . In this regard, C3 deficiency has been associated with a reduced antigen- presenting capac-ity of APCs (lower expression of MHC class II molecules and impaired co-stimulation via CD80 and CD86), with important implications for autoimmune conditions and antitumour immunity  40 . Notably, the absence of C3aR or C5aR1 stimulation at the APC–T cell interface has been shown to negatively affect the survival of CD4 +  T cells 41 . Moreover, genetic or pharmaco logical ablation of C3aR or C5aR1 signalling has also been linked to the induction of an immunosuppressive pheno type in CD4 +  T cells in a manner that could diminish the magnitude of anti tumour effector T cell responses 42 .Further insight into the fundamental role of com-plement in immune cell homeostasis has been provided by studies describing an intracellular complement cir-cuitry in CD4 +  T cells that modulates cell differentiation through its crosstalk with the NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome and the generation of reactive oxygen species (ROS) 38,43 . Taken together, these studies support the presence of a consti-tutively active complement circuitry within lymphocytes that has a role in the maintenance of the T cell pool in the periphery and may also potentiate effector T cell responses in the context of tumour immunotherapy. Complement and cancer vaccines.   Cancer vaccines represent another promising modality in cancer immuno therapy, and several studies have indicated that complement activation may contribute to vaccine efficacy through enhanced antigen uptake and co- stimulatory signalling 44 . Indeed, C5a has been shown to potentiate antigen processing and presentation by human DCs 45,46 . In this context, a C5a-derived C5aR1 agonist fused to a peptide-based cancer vaccine has been tested in a preclinical model of melanoma, with encouraging results 47 . These studies point to a different therapeutic perspective whereby harnessing complement activation and triggering C5aR1-dependent signalling on tumour antigen-loaded DCs may help patients elicit potent anti-tumour immune responses. From a different standpoint, the function of the opsonin C3dg as a molecular adjuvant that lowers the activation threshold of B cells and the role of C3-derived fragments in promoting antigen retention by follicular DCs and boosting memory responses have long been appreciated as mechanisms bridging innate and adaptive immune responses 48 . However, this fun-damental facet of complement biology has not been rigorously investigated in the context of cancer immuno-therapy. These key immunoregulatory activities of com-plement may have important implications for tumour immunotherapy and may be worth exploring during the design of antitumour vaccines. Complement and radiotherapy.   Alongside surgical resection and chemotherapy, radiotherapy is also rec-ognized as a clinical mainstay of cancer treatment, espe-cially in the context of very aggressive tumours with poor prognosis 49 . Recent evidence supports a causative asso-ciation between radiation-induced tumour cell damage, the tumour-derived pro-inflammatory milieu and the potentiation of antitumour immunity  50,51 . Interestingly, radiotherapy-induced cell death was recently shown to induce transient complement activation within solid tumours, with both tumour cells and infiltrating immune cells serving as sources of complement protein produc-tion 52 . More importantly, radiotherapy was found to upregulate the release of C3a and C5a within the tumour microenvironment, inducing potent DC responses and subsequently leading to pronounced infiltration of CD8 +  effector T cells into the irradiated tumours 52 . Notably, an Box 2 |  Complement: numerous proteins, plenty of functions Soluble complement proteins are primarily produced in the liver (the exceptions being C1q and Factor D, which are secreted mainly by macrophages and adipocytes, respectively) 55 . Whereas the major ‘pool’ of complement is located in the blood, a variety of cell types, including fibroblasts, adipocytes and endothelial and immune cells, secrete complement proteins. A boost in complement production is often observed during inflammatory and pathologic conditions, so that virtually any tissue can be surrounded by complement activation products 13 . Such a notion of local complement is key to perceiving how imbalanced complement activation affects pathology in distinct tissues, from the skin to the kidneys, from the lung to the brain, and influences the fate of an assortment of tumour cells 3,17,126 . Essentially, the presence of a trigger or improper regulation results in the production of activation fragments (BOX 1)  that can bind to their respective receptors on cell surfaces and elicit biological responses. Upon complement activation, C3 fragments (that is, C3b, iC3b and C3dg) that are associated with antigens bind to the complement receptors CR1 (CD35), CR3 (CD11b and CD18), CR4 (CD11c and CD18) and/or CRIg, inducing phagocytosis and modulating the function of antigen-presenting cells 13 . In turn, triggering of CR2 by iC3b and C3dg is associated with the activation of B cells 35 . Furthermore, signalling through the G protein-coupled anaphylatoxin receptors C3aR, in the case of C3a, or C5aR1 (also known as CD88), in the case of C5a and desarginated C5a (C5a-desArg), regulates cell activation, degranulation, proliferation and cytokine responses, which are essential for initiating and maintaining inflammatory responses 36 . In addition, adaptive immune responses are modulated when membrane cofactor protein (MCP, also known as CD46) is triggered on T cells 132 . Such an array of interactions between complement proteins and cell-surface receptors not only guarantees immune surveillance but also determines the outcome of immune responses, metabolic pathways and developmental processes. Proper control of the activation signals described above is required to prevent excessive activation that can lead to tissue damage and is achieved by an assortment of complement regulators (TABLE 1)  that restrain certain steps of the complement cascade 133 . REVIEWS  4 |  ADVANCE ONLINE PUBLICATION www.nature.com/nri © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
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