Complement in cancer: untangling an intricate relationship

Key Points

  • Complement potentiates various forms of cancer therapy, including antibody-mediated cytotoxicity, vaccines and radiotherapy.

  • Complement-dependent cytotoxicity can be improved by optimizing antibody dosing schemes and through the development of dual-target antibodies.

  • Imbalanced complement activation promotes inflammation and tumorigenesis, triggering mechanisms of tumour cell proliferation, migration, invasiveness and metastasis.

  • Novel insights into mechanisms triggering local complement activation in the tumour microenvironment are highly anticipated.

  • The feasibility of using complement-based biomarkers for cancer prognosis and diagnosis is still controversial.

  • Combined targeting of complement and immune checkpoint pathways has considerable therapeutic potential.

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.

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Figure 1: Complement mediates tumour cytolysis in the context of antibody-based immunotherapy.
Figure 2: Complement activation in the tumour microenvironment promotes tumorigenesis.

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Acknowledgements

We thank D. McClellan for editorial assistance. J.D.L. also thanks R. Weaver and S. Weaver for the generous endowment of his professorship. Given the broad scope of this review, we often refer to specialized review articles rather than primary literature, and we have been able to include only selected examples of the breadth of the transformative work in the field; we therefore want to thank all our colleagues who are not specifically cited for their contributions and their understanding. This work was supported by grants from the U.S. National Institutes of Health (AI068730, AI030040) and the National Science Foundation (grant No. 1423304) and by funding from the European Community's Seventh Framework Programme, under grant agreement number 602699 (DIREKT).

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E.S.R. researched the literature and wrote and edited the manuscript. D.C.M. researched the literature and wrote and edited the manuscript. D.R. edited the manuscript and contributed to discussions of the content. A.M. edited the manuscript and contributed to discussions of the content. J.D.L. wrote and edited the manuscript and contributed to discussions of the content. E.S.R. and D.C.M. contributed equally to writing the manuscript and to reviewing and editing the manuscript before submission.

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Correspondence to John D. Lambris.

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Competing interests

J.D.L. and D.R. are inventors of patents or patent applications that describe the use of complement inhibitors for therapeutic purposes. J.D.L. is the founder of Amyndas Pharmaceuticals, which is developing complement inhibitors. E.S.R. and D.C.M. declare no financial interest or conflict.

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Reis, E., Mastellos, D., Ricklin, D. et al. Complement in cancer: untangling an intricate relationship. Nat Rev Immunol 18, 5–18 (2018). https://doi.org/10.1038/nri.2017.97

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