EDITORIAL

published: 11 February 2020

doi: 10.3389/fimmu.2020.00139

Editorial: The Role of Complement in

Tumors
Barbara E. Rolfe 1*, Ruben Pio 2 , Trent M. Woodruff 3 , Maciej M. Markiewski 4 and
Helga D. Manthey 1
1
Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia,
2
Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain, 3 School of Biomedical Sciences, The
University of Queensland, Brisbane, QLD, Australia, 4 Department of Immunotherapeutics and Biotechnology, School of
Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX, United States

Keywords: complement, cancer, metastasis, C5b-9, C1q, C3a, C5a, complement regulatory proteins

Editorial on the Research Topic

The Role of Complement in Tumors

Activation of the complement system is one of the earliest responses to invading pathogens and
tissue damage (1). Complement activation leads to production of a range of effectors including the
opsonin C3b, the anaphylatoxins C3a and C5a, and the C5b-9 complex (membrane attack complex;
MAC) (2, 3). In addition to potent innate immune activities, complement effector systems also
contribute to efficient adaptive immune responses (4). While critical to proper immune function,
inappropriate or excessive complement activation contributes to many pathological inflammatory
conditions (5), including cancer. As described in this issue, the complement system is increasingly
recognized as a double-edged sword: on the one hand contributing to the anti-tumor response, but
Edited and reviewed by: on the other protecting the tumor against immune attack and promoting metastasis.
Catherine Sautes-Fridman,
INSERM U1138 Centre de Recherche
des Cordeliers, France COMPLEMENT-DEPENDENT CYTOTOXICITY AND C5b-9
*Correspondence: (MEMBRANE ATTACK COMPLEX)
Barbara E. Rolfe
b.rolfe@uq.edu.au As described by Macor et al., the complement system has long been recognized to contribute to
anti-tumor defense mechanisms via complement dependent cytotoxicity (CDC) (6) and antibody-
Specialty section: dependent cell mediated cytotoxicity (ADCC) (7). The introduction of recombinant antibodies
This article was submitted to for cancer treatment has led to renewed interest in complement as an anti-tumor defense system.
Cancer Immunity and Immunotherapy, The protective role of complement in cancer is discussed, with focus on the beneficial effect of
a section of the journal
complement-fixing antibodies which initiate cancer cell killing via CDC.
Frontiers in Immunology
The cytotoxic activities of C5b-9, and the mechanisms by which it damages cancer cells, are
Received: 14 January 2020 further discussed by Fishelson and Kirschfink, along with the multiple mechanisms that tumor
Accepted: 20 January 2020
cells employ to resist C5b-9-induced death. They discuss the potential for therapeutic approaches
Published: 11 February 2020
to counter tumor escape mechanisms and potentiate antibody-based immunotherapies, but caution
Citation: that intervention strategies to augment complement activation could also worsen outcomes.
Rolfe BE, Pio R, Woodruff TM,
Although C5b-9 has traditionally been attributed an anti-tumoral role through CDC, Vlaicu
Markiewski MM and Manthey HD
(2020) Editorial: The Role of
et al. review the evidence that C5b-9 at a sub-lytic dose stimulates tumor growth. Hence
Complement in Tumors. strategies to counteract the tumor-promoting traits of C5b-9 and potentiate anti-tumoral actions
Front. Immunol. 11:139. (including enhanced efficacy of antibody-based immunotherapy) may be the next major direction
doi: 10.3389/fimmu.2020.00139 for immuno-oncology.

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Rolfe et al. Editorial: The Role of Complement in Tumors

COMPLEMENT REGULATORY PROTEINS responses, but is also crucial to metastasis, endowing tumor
cells with properties required for metastatic dissemination and
As described by Geller and Yan, membrane and soluble establishment. Complement activation products (primarily C3a
complement regulatory proteins (CRPs) prevent excessive and C5a) induce a range of mediators which promote epithelial-
complement activation. Therefore, over-expression of CRPs by mesenchymal transition, tumor growth, invasion, dissemination
tumor cells protects them against complement-mediated attack, via lymphatic and circulatory systems, and also protect cells
interferes with anti-tumor therapies, and enhances metastatic within the metastatic niche. The authors highlight the potential
potential. The application of CRPs as prognostic biomarkers of complement-targeting drugs to augment the clinical efficacy of
and therapeutic targets is discussed, along with the potential for current immunotherapies and effectively eradicate both primary
combinatorial approaches with other anti-tumor therapies. tumors and distant metastases.

COMPLEMENT C1q CONCLUSIONS

The first subcomponent of the classical complement pathway, Despite recent clinical advances in cancer immunotherapy,
C1q is a pattern recognition molecule locally synthesized by the estimated percentage of patients responding to checkpoint
macrophages and dendritic cells (8). Bioinformatics analysis by inhibitors in the United States in 2018 was only 12.46% (11).
Mangogna et al. suggests C1q as a new prognostic biomarker for Hence there remains an urgent need for novel therapeutic
several cancers. strategies to boost response rates. As a critical link between
the innate and adaptive immune systems, the complement
ANAPHYLATOXINS C3a AND C5a system is a promising therapeutic target. However, knowledge
is the key to realizing the clinical potential of complement-
Since the seminal paper of Markiewski et al. (9) identifying a targeting therapeutics. Only a thorough understanding of the
role for C5a in promoting tumor progression, similar effects role of complement pathways in the tumor microenvironment
have been demonstrated in a range of murine cancer models. will enable development of strategies to selectively (and
Wang et al. propose C3aR and C5aR1 as a new class of safely) target the pro-tumor effects of complement, while
immune checkpoints. They discuss findings suggesting that simultaneously augmenting the anti-tumor effects. To quote
C3aR/C5aR signaling regulates T cell mediated antitumor Fishelson and Kirschfink, “currently we perceive only the
immunity via transcriptional suppression of interleukin (IL)- tip of the ice-berg of . . . interactions between cancer cells
10. Given resistance of the majority of patients to the current and complement components.” Indeed, given the diversity of
forms of immunotherapy, and adverse reactions associated with responses, therapeutic protocols will likely need to be optimized
these approaches, the authors suggest the manipulation of the for each cancer type and stage, and possibly for individual cancer
C3aR/C5aR/IL-10 pathway as an alternative strategy for cancer. patients, depending on their “immune history.”
Lenkiewicz et al. discovered that C3 and C5 cleavage
fragments enhance trafficking, motility and, therefore, AUTHOR CONTRIBUTIONS
dissemination of malignant cells in hematologic malignancies
through a p38 MAPK and inducible heme oxygenase 1 All authors contributed to the conception and design of this
(HO-1) manner. They propose that activation of the work. BR drafted the manuscript, the other editors RP, TW,
complement cascade in patients with these malignancies (e.g., MM, and HM provided critical revisions and approved the
triggered by infection) can contribute to faster dissemination submitted manuscript.
of disease. Thus, targeting this pathway may ameliorate
dissemination of leukemic cells and improve clinical outcomes in FUNDING
these patients.
Kleczko et al. discuss the potential for complement BR, RP, TW, and HM acknowledge support from grants
targeting therapies for the treatment of intractable cancers, from the Australian National Health and Medical Research
in particular lung cancer. They review the mechanisms by Council (NHMRC; APP1103951 and APP1164202) and Cancer
which the anaphylatoxins C3a and C5a influence tumor growth Council Queensland (CCQ). RP was supported by the AECC
and promote epithelial-mesenchymal transition and tumor Scientific Foundation, and Fondo de Investigación Sanitaria-
metastasis. Since complement proteins can regulate both pro- Fondo Europeo de Desarrollo Regional Una manera de hacer
and anti-tumorigenic pathways, the authors stress the need to Europa (PI17/00411) and MM by the National Institute of
better understand the effects of complement activation within Health (R01CA190209).
tumor tissue, and how this may be influenced by different
oncogenic drivers. ACKNOWLEDGMENTS
Cancer metastasis is estimated to be responsible for greater
than 90% of cancer deaths (10). As discussed by Ajona We thank all the authors for their contributions to this Research
et al., distorted complement homeostasis not only remodels Topic. We also thank the reviewers for their evaluation of
the tumor microenvironment by inhibiting anti-tumor immune the manuscripts.

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Rolfe et al. Editorial: The Role of Complement in Tumors

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