Review

Complement in cancer: untangling an intricate relationship

Published online:

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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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).

Author information

Author notes

    • Edimara S. Reis
    •  & Dimitrios C. Mastellos

    These authors contributed equally to this work.

Affiliations

  1. Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania 19104, Philadelphia, Pennsylvania, USA.

    • Edimara S. Reis
    •  & John D. Lambris
  2. National Center for Scientific Research 'Demokritos', Athens 15310, Greece.

    • Dimitrios C. Mastellos
  3. Department of Pharmaceutical Sciences, University of Basel, Basel 4056, Switzerland.

    • Daniel Ricklin
  4. Humanitas Clinical and Research Center and Humanitas University, Rozzano-Milan 20089, Italy.

    • Alberto Mantovani

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Contributions

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.

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.

Corresponding author

Correspondence to John D. Lambris.