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  • Review Article
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Context-dependent roles of complement in cancer

Abstract

The tumour microenvironment (TME) highly influences the growth and spread of tumours, thus impacting the patient’s clinical outcome. In this context, the complement system plays a major and complex role. It may either act to kill antibody-coated tumour cells, support local chronic inflammation or hamper antitumour T cell responses favouring tumour progression. Recent studies demonstrate that these opposing effects are dependent upon the sites of complement activation, the composition of the TME and the tumour cell sensitivity to complement attack. In this Review, we present the evidence that has so far accrued showing a role for complement activation and its effects on cancer control and clinical outcome under different TME contexts. We also include a new analysis of the publicly available transcriptomic data to provide an overview of the prognostic value of complement gene expression in 30 cancer types. We argue that the interplay of complement components within each cancer type is unique, governed by the properties of the tumour cells and the TME. This concept is of critical importance for the design of efficient therapeutic strategies aimed at targeting complement components and their signalling.

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Fig. 1: The complement system in the tumour microenvironment.
Fig. 2: The pro-tumoural and antitumoural impact of complement on the immune contexture.
Fig. 3: The pro-tumoural and antitumoural impact of complement on neoangiogenesis and the biology of tumour cells.
Fig. 4: Expression of complement genes in human cancers.
Fig. 5: Impact of the expression level of complement genes on the survival of patients with cancer.
Fig. 6: Proposed mechanism of classical complement pathway activation and its consequences on tumour progression in tumours with ‘aggressive complement’.

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Acknowledgements

This work was supported by grants from Pierre Fabre Research Institute (to W.H.F. and L.T.R.); the Association pour la Recherche sur le Cancer (ARC), the Cartes d’Identité des Tumeurs (CIT) programme from the Ligue Nationale Contre le Cancer (RS19/75-111) and Cancer Research for Personalized Medicine (CARPEM) (to L.T.R.); and the Institut National du Cancer (INCa) (HTE Plan Cancer (C1608DS) and PRTK G26 NIVOREN) and the Association pour la recherche de thérapeutiques innovantes en cancérologie (ARTIC, BioniKK programme) (to C.S.-F.). This work was also supported by INSERM, University of Paris, Sorbonne University, CARPEM T8 and the Labex Immuno-Oncology Excellence Program. M.V.D. received a PhD fellowship from ARC, and F.P. received a doctoral fellowship from CARPEM.

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L.T.R., M.V.D. and F.P. researched data for the article. M.V.D. performed the transcriptomic analyses and designed the figures. L.T.R., M.V.D., C.S.-F. and W.H.F. provided a substantial contribution to discussions of the content. L.T.R., M.V.D. and W.H.F. contributed to writing the article and all authors contributed to reviewing and editing the manuscript before submission.

Corresponding authors

Correspondence to Lubka T. Roumenina or Wolf Herman Fridman.

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Competing interests

L.T.R and W.H.F received research funding from the Research Institute of Pierre Fabre. M.V.D, F.P. and C.S-F declare no competing interests.

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Nature Reviews Cancer thanks V. Afshar-Khargan, C. Kemper and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Anaphylatoxins

The collective name for the complement activation fragments C3a, C4a and C5a.

Oxidative burst

A rapid release of reactive oxygen species (superoxide radicals and hydrogen peroxide) from different types of cells.

Mortalin

A highly conserved heat shock protein implicated in functions ranging from the stress response to control of cell proliferation and inhibition of apoptosis.

Autophagy

A cellular stress response in which cellular proteins and organelles are digested and recycled by lysosomes in order to maintain active metabolism.

NETosis

A process of release of neutrophil extracellular traps (NETs) from overactivated neutrophils. NETs are defensive networks of extracellular fibres, primarily composed of DNA and histones.

Leptomeningeal metastasis

A complication occurring when tumour cells spread to the leptomeninges, membranes lining the brain and spinal cord, enclosing the cerebrospinal fluid.

Tertiary lymphoid structures

Ectopic lymphoid aggregates that reflect lymphoid neogenesis occurring in tissues at sites of inflammation. These structures are detected in tumours where they orchestrate local and systemic antitumour responses.

Endothelial quiescence

The resting state of the endothelium, enabling it to exert its barrier functions, preventing thrombosis and inflammation. In the context of cancer, quiescent endothelium establishes a barrier that prevents T cells from efficiently penetrating the tumour.

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Roumenina, L.T., Daugan, M.V., Petitprez, F. et al. Context-dependent roles of complement in cancer. Nat Rev Cancer 19, 698–715 (2019). https://doi.org/10.1038/s41568-019-0210-0

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