REVIEWS Complement in cancer: untangling an intricate relationship Edimara S. Reis1*, Dimitrios C. Mastellos2*, Daniel Ricklin3, Alberto Mantovani4 and John D. Lambris1 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. An enormous body of data produced by converging indicated, however, that this versatile innate immune disciplines has provided unprecedented insight into the effector system mediates key homeostatic functions in intricate and dynamic relationship that exists between processes ranging from early vertebrate development developing tumours and the host immune system1–3. and tissue morphogenesis to tissue regeneration, cen­ It is widely accepted that neoplastic transformation is tral nervous system synaptic pruning, host–microbiota a multifactorial process that the immune system can symbiosis and adaptive immune regulation14–17. In the detect through genetic and epigenetic changes that context of cancer immunotherapy, complement can alter the antigenic signatures of tumour cells. Control be readily triggered into action by damage­associated of tumour growth relies on both innate and adaptive molecular patterns (DAMPs) exposed on the surface mechanisms of immunosurveillance and is subject to the of tumour cells3,6. Although the role of complement selective pressure exerted by distinct immuno regulatory as an effector mechanism that potentiates antibody-­ 4–7 1Department of Pathology pathways in the tumour microenvironment . In this dependent tumour cytolysis has been long appreciated, and Laboratory Medicine, regard, cancer treatment has been revolutionized by clinical challenges, such as the upregulation of a wide School of Medicine, University new immuno modulatory approaches that elicit durable spectrum of complement regulatory proteins, remain to of Pennsylvania 19104, clinical responses in cancer patients by restoring anti­ be addressed12,18,19. Philadelphia, Pennsylvania, USA. tumour immunity and potentiating standard therapeutic Clearly, the role of complement as an effector 5,8 2National Center for Scientific regimens, such as tumour radiotherapy . of tumour cytotoxic responses remains relevant to Research ‘Demokritos’, Elements of the innate immune response are inte­ antibody­ mediated immunotherapy, guiding new thera­ Athens 15310, Greece. gral components of antitumour effector mechanisms3,9. peutic options. Intriguingly, however, accumu lating 3 Department of In many ways, tumour cells are perceived by the innate evidence from studies published in the past decade Pharmaceutical Sciences, University of Basel, immune system as noxious, ‘non­self’ matter that must has pointed to a fascinating paradigm shift: the real­ 10 Basel 4056, Switzerland. be disposed of . Therefore, potent antitumour cytotoxic ization that complement activation within the tumour 4Humanitas Clinical and responses are elicited by innate immune cells, followed microenvironment can serve a tumour­promoting Research Center and by elimination of opsonized tumour cells through the role by perpetuating local T cell immuno suppression Humanitas University, Rozzano-Milan 20089, Italy. concerted action of tumour­directed antibodies and and chronic inflammation that promotes tumour 9,11,12 20–23 *These authors contributed complement . Complement is a phylogenetically immune escape, outgrowth and metastasis . Diverse equally to this work. conserved branch of the innate immune response that complement-­derived effectors and downstream sig­ Correspondence to J.D.L. has traditionally been perceived as a network of proteins nalling partners have been implicated in processes [email protected] that rapidly respond to microbial intruders, triggering ranging from tumour cell anchorage and proliferation doi:10.1038/nri.2017.97 the release of inflammatory mediators, phagocytic to tumour­associated angiogenesis, matrix remodel­ Published online 18 Sep 2017 responses and cell lysis13 (BOX 1). Growing evidence has ling, migration, tissue invasiveness and metastasis6,19. NATURE REVIEWS | IMMUNOLOGY VOLUME 18 | JANUARY 2018 | 5 ©2017 Mac millan Publishers Li mited, part of Spri nger Nature. All ri ghts reserved. REVIEWS Box 1 | An overview of the complement system The complement system comprises an extensive network of fluid-phase of interaction with diverse immune effectors127. Notably, the spontaneous and membrane-bound glycoproteins, cofactors, receptors and regulatory low-level hydrolysis of C3 keeps the alternative pathway in ‘standby’ mode proteins that engage in innate immune recognition, adaptive cell to allow for rapid amplification upon microbial challenge128. Complement stimulation and pro-inflammatory effector responses126. Being a crucial activation culminates in the assembly of short-lived multiprotein mediator of tissue immunosurveillance, complement responds rapidly to complexes with enzymatic activity termed ‘convertases’. These enzymes molecular stress signals through a cascade of sequential proteolytic are responsible for the proteolytic activation of the central components reactions initiated by the binding of pattern recognition molecules C3 and C5 and the release of their respective bioactive fragments, C3a (for example, C1q, mannose-binding lectin (MBL), MBL-associated serine and C3b, and C5a and C5b. The rapid amplification of C3b deposition via proteases (MASPs), ficolins and properdin (also known as Factor P)) to the alternative pathway is a process known to underlie several clinical distinct structures on damaged cells, biomaterial surfaces or microbial disorders associated with genetic or acquired complement dysregulation intruders17. Whereas three ‘canonical’ pathways of activation have been (for example, C3 glomerulopathy)17,129. Cleavage of C5 leads to the release described to date (that is, the classical, alternative and lectin pathways), of the potent inflammatory mediator C5a and initiates a sequence of mounting evidence indicates that complement can be activated via protein–protein interactions that induces assembly of the membrane multiple routes, depending on the initiating triggers and the distinct attack complex (MAC, C5b–C9), a multiprotein ‘pore’ with cell activating microenvironment or pathophysiological context126. The classical pathway and cytolytic properties. Unconventional routes of complement activation is initiated by binding to circulating or surface-bound immune complexes, include the deployment of proteolytic enzymes of the coagulation and while the lectin and alternative pathways are triggered by pathogen- fibrinolytic systems that can efficiently cleave both C3 and C5 into their associated molecular patters (PAMPs) or aberrant carbohydrate structures bioactive fragments130. These non-canonical routes of activation, in on damaged or necrotic cells. All activation pathways converge at the conjunction with the intracellular complement circuitry38,131, define a cleavage of C3, an abundant plasma protein that undergoes elaborate broader pathophysiological base of triggering cues that can initiate conformational changes upon activation, thereby exposing multiple sites homeostatic or disease-tailored complement responses. Extrinsic protease pathway Convertases Unconventional C3b C3bBb routes of activation Properdin Factor B C3a Factor D C3 Terminal (lytic) pathway C3(H20)Bb C3bBb3b C3 C3(H 0) 2 C5a Alternative pathway ‘tick-over’ C3 C3b C5 C5b C5b–C9 MAC Factor D MBL Ficolins C6 MASPs Factor B C4b2b3b C7 C3bBb C8 C2 C9n Lectin pathway C4b2b C4 Alternative pathway amplification loop C1q C1r C1s Intracellular complement circuitry Classical pathway Nature Reviews | Immunology With new insights being gained from a variety of tumour immunotherapies and interrogate the feasibility of using models, it is becoming clear that the contribution of com­ complement­based biomarkers for cancer diagnosis, plement to cancer pathophysiology is far more complex tumour staging and prognosis. than originally thought and appears to be largely contex­ tual, depending on several factors, such as the cellular Complementing cancer immunotherapy origin of the tumour in question, its inherent capacity There is a growing appreciation that durable clinical to produce autologous complement proteins, the nature responses in patients with cancer are more likely to be of the tumour microenvironment and the magnitude of achieved when targeted therapies that ablate key onco­ complement activation. genic signalling pathways are combined with approaches In this Review, we discuss current and emerging that effectively reverse tumour­instigated immuno­ aspects of complement’s contribution to cancer elim­ suppression and augment antitumour immunity — an ination and progression and suggest therapeutic