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The Role of Complement in Cancer Immunotherapy

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A special issue of Antibodies (ISSN 2073-4468).

Deadline for manuscript submissions: closed (15 August 2020) | Viewed by 69334

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Special Issue Editor

Prof. Dr. Ronald P. Taylor

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Guest Editor

Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesvile, VA 22908, USA
Interests: ADCC; CDC; complement and Fc receptors; immunotherapy of cancer; antigenic modulation

Special Issue Information

Dear Colleagues,

The dual role of complement in either the development or therapy of cancer has been investigated extensively and is characterized by a substantial literature which documents conditions in which complement can either enhance tumor growth or promote killing of malignant cells. Indeed, there are now numerous examples of monoclonal antibodies (mAbs), either approved by the FDA, or under active investigation, which make use of complement in eliminating cancer cells. Although direct in vitro killing of mAb-opsonized cancer cell lines by complement-dependent cytotoxicity (CDC) can be readily demonstrated, challenges to translate these findings to the clinic are considerable and numerous strategies are being employed to maximize mAb-mediated CDC in cancer treatment. These approaches include: redesign of mAb dosing schedules; engineering the Fc regions of the mAbs to enhance complement activation; treatment with cocktails of mAbs that bind to several different sites on the targeted cells and thus potentially synergize in promoting CDC; and also neutralizing complement control proteins on malignant cells to weaken their defenses against complement. Target sites on malignant cells that have been successfully exploited for mAb-induced CDC include CD20, CD37, CD38, CD52, and Epidermal Growth Factor Receptors. MAbs specific for complement components have served as powerful analytical reagents to investigate the detailed mechanisms of CDC, and they have been employed to document complement activation by cancer cells and to examine the role of complement proteins (in particular C1q and fragments of C3 and C5) in supporting tumor growth. The use of polyclonal and mAb reagents has revealed a role for the intracellular complement system in cancer biology, and strategies that focus on the interaction of complement with the tumor microenvironment and examine the impact of the complotype on the response to immunotherapy in cancer should lead to additional mAb-based therapies. Along these lines, there is now increasing evidence that strategies which make use of mAbs or other agents to modulate the action of C3a/C5a or their respective receptors may also find use in cancer immunotherapy.

Prof. Dr. Ronald P. Taylor
Guest Editor

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Keywords

angiogenesis
B cell malignancies
calcium fluxes
complement control proteins
complotype
gC1qR
intracellular complement system
mouse models
targeting CD19

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Published Papers (11 papers)

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Editorial

Jump to: Research, Review

4 pages, 164 KiB

Open AccessEditorial

Special Issue: The Role of Complement in Cancer Immunotherapy

by Ronald P. Taylor

Antibodies 2021, 10(3), 29; https://doi.org/10.3390/antib10030029 - 23 Jul 2021

Viewed by 2879

Abstract

The complement system plays an important role in critical aspects of immune defense and in the maintenance of homeostasis in the bloodstream, as well as in essentially all tissues and organs [...] Full article

(This article belongs to the Special Issue The Role of Complement in Cancer Immunotherapy)

Research

Jump to: Editorial, Review

12 pages, 1657 KiB

Open AccessFeature PaperArticle

An Immunoregulatory Role for Complement Receptors in Murine Models of Breast Cancer

by Fazrena Nadia Md Akhir, Mohd Hezmee Mohd Noor, Keith Weng Kit Leong, Jamileh A. Nabizadeh, Helga D. Manthey, Stefan E. Sonderegger, Jenny Nga Ting Fung, Crystal E. McGirr, Ian A. Shiels, Paul C. Mills, Trent M. Woodruff and Barbara E. Rolfe

Antibodies 2021, 10(1), 2; https://doi.org/10.3390/antib10010002 - 8 Jan 2021

Cited by 10 | Viewed by 5140

Abstract

The complement system has demonstrated roles in regulating tumor growth, although these may differ between tumor types. The current study used two murine breast cancer models (EMT6 and 4T1) to investigate whether pharmacological targeting of receptors for complement proteins C3a (C3aR) and C5a (C5aR1) is protective in murine breast cancer models. In contrast to prior studies in other tumor models, treatment with the selective C5aR1 antagonist PMX53 had no effect on tumor growth. However, treatment of mice with a dual C3aR/C5aR1 agonist (YSFKPMPLaR) significantly slowed mammary tumor development and progression. Examination of receptor expression by quantitative polymerase chain reaction (qPCR) analysis showed very low levels of mRNA expression for either C3aR or C5aR1 by EMT6 or 4T1 mammary carcinoma cell lines compared with the J774 macrophage line or bone marrow-derived macrophages. Moreover, flow cytometric analysis found no evidence of C3aR or C5aR1 protein expression by either EMT6 or 4T1 cells, leading us to hypothesize that the tumor inhibitory effects of the dual agonist are indirect, possibly via regulation of the anti-tumor immune response. This hypothesis was supported by flow cytometric analysis of tumor infiltrating leukocyte populations, which demonstrated a significant increase in T lymphocytes in mice treated with the C3aR/C5aR1 agonist. These results support an immunoregulatory role for complement receptors in primary murine mammary carcinoma models. They also suggest that complement activation peptides can influence the anti-tumor response in different ways depending on the cancer type, the host immune response to the tumor and levels of endogenous complement activation within the tumor microenvironment. Full article

(This article belongs to the Special Issue The Role of Complement in Cancer Immunotherapy)

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15 pages, 1663 KiB

Open AccessFeature PaperArticle

Enhancing CDC and ADCC of CD19 Antibodies by Combining Fc Protein-Engineering with Fc Glyco-Engineering

by Sophia Roßkopf, Klara Marie Eichholz, Dorothee Winterberg, Katarina Julia Diemer, Sebastian Lutz, Ira Alexandra Münnich, Katja Klausz, Thies Rösner, Thomas Valerius, Denis Martin Schewe, Andreas Humpe, Martin Gramatzki, Matthias Peipp and Christian Kellner

Antibodies 2020, 9(4), 63; https://doi.org/10.3390/antib9040063 - 17 Nov 2020

Cited by 22 | Viewed by 6928

Abstract

Background: Native cluster of differentiation (CD) 19 targeting antibodies are poorly effective in triggering antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), which are crucial effector functions of therapeutic antibodies in cancer immunotherapy. Both functions can be enhanced by engineering the antibody’s Fc region by altering the amino acid sequence (Fc protein-engineering) or the Fc-linked glycan (Fc glyco-engineering). We hypothesized that combining Fc glyco-engineering with Fc protein-engineering will rescue ADCC and CDC in CD19 antibodies. Results: Four versions of a CD19 antibody based on tafasitamab’s V-regions were generated: a native IgG1, an Fc protein-engineered version with amino acid exchanges S267E/H268F/S324T/G236A/I332E (EFTAE modification) to enhance CDC, and afucosylated, Fc glyco-engineered versions of both to promote ADCC. Irrespective of fucosylation, antibodies carrying the EFTAE modification had enhanced C1q binding and were superior in inducing CDC. In contrast, afucosylated versions exerted an enhanced affinity to Fcγ receptor IIIA and had increased ADCC activity. Of note, the double-engineered antibody harboring the EFTAE modification and lacking fucose triggered both CDC and ADCC more efficiently. Conclusions: Fc glyco-engineering and protein-engineering could be combined to enhance ADCC and CDC in CD19 antibodies and may allow the generation of antibodies with higher therapeutic efficacy by promoting two key functions simultaneously. Full article

(This article belongs to the Special Issue The Role of Complement in Cancer Immunotherapy)

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12 pages, 6146 KiB

Open AccessArticle

Anti gC1qR/p32/HABP1 Antibody Therapy Decreases Tumor Growth in an Orthotopic Murine Xenotransplant Model of Triple Negative Breast Cancer

by Ellinor I. Peerschke, Elisa de Stanchina, Qing Chang, Katia Manova-Todorova, Afsar Barlas, Anne G. Savitt, Brian V. Geisbrecht and Berhane Ghebrehiwet

Antibodies 2020, 9(4), 51; https://doi.org/10.3390/antib9040051 - 6 Oct 2020

Cited by 7 | Viewed by 4703

Abstract

gC1qR is highly expressed in breast cancer and plays a role in cancer cell proliferation. This study explored therapy with gC1qR monoclonal antibody 60.11, directed against the C1q binding domain of gC1qR, in a murine orthotopic xenotransplant model of triple negative breast cancer. MDA231 breast cancer cells were injected into the mammary fat pad of athymic nu/nu female mice. Mice were segregated into three groups (n = 5, each) and treated with the vehicle (group 1) or gC1qR antibody 60.11 (100 mg/kg) twice weekly, starting at day 3 post-implantation (group 2) or when the tumor volume reached 100 mm³ (group 3). At study termination (d = 35), the average tumor volume in the control group measured 895 ± 143 mm³, compared to 401 ± 48 mm³ and 701 ± 100 mm³ in groups 2 and 3, respectively (p < 0.05). Immunohistochemical staining of excised tumors revealed increased apoptosis (caspase 3 and TUNEL staining) in 60.11-treated mice compared to controls, and decreased angiogenesis (CD31 staining). Slightly decreased white blood cell counts were noted in 60.11-treated mice. Otherwise, no overt toxicities were observed. These data are the first to demonstrate an in vivo anti-tumor effect of 60.11 therapy in a mouse model of triple negative breast cancer. Full article

(This article belongs to the Special Issue The Role of Complement in Cancer Immunotherapy)

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Review

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14 pages, 1330 KiB

Open AccessFeature PaperReview

Complement Activation in the Treatment of B-Cell Malignancies

by Clive S. Zent, Jonathan J. Pinney, Charles C. Chu and Michael R. Elliott

Antibodies 2020, 9(4), 68; https://doi.org/10.3390/antib9040068 - 1 Dec 2020

Cited by 6 | Viewed by 5488

Abstract

Unconjugated monoclonal antibodies (mAb) have revolutionized the treatment of B-cell malignancies. These targeted drugs can activate innate immune cytotoxicity for therapeutic benefit. mAb activation of the complement cascade results in complement-dependent cytotoxicity (CDC) and complement receptor-mediated antibody-dependent cellular phagocytosis (cADCP). Clinical and laboratory studies have showed that CDC is therapeutically important. In contrast, the biological role and clinical effects of cADCP are less well understood. This review summarizes the available data on the role of complement activation in the treatment of mature B-cell malignancies and proposes future research directions that could be useful in optimizing the efficacy of this important class of drugs. Full article

(This article belongs to the Special Issue The Role of Complement in Cancer Immunotherapy)

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14 pages, 2235 KiB

Open AccessReview

The Role of Complement in Angiogenesis

by Maciej M. Markiewski, Elizabeth Daugherity, Britney Reese and Magdalena Karbowniczek

Antibodies 2020, 9(4), 67; https://doi.org/10.3390/antib9040067 - 1 Dec 2020

Cited by 18 | Viewed by 6271

Abstract

The link of the complement system to angiogenesis has remained circumstantial and speculative for several years. Perhaps the most clinically relevant example of possible involvement of complement in pathological neovascularization is age-related macular degeneration. Recent studies, however, provide more direct and experimental evidence that indeed the complement system regulates physiological and pathological angiogenesis in models of wound healing, retinal regeneration, age-related macular degeneration, and cancer. Interestingly, complement-dependent mechanisms involved in angiogenesis are very much context dependent, including anti- and proangiogenic functions. Here, we discuss these new developments that place complement among other important regulators of homeostatic and pathological angiogenesis, and we provide the perspective on how these newly discovered complement functions can be targeted for therapy. Full article

(This article belongs to the Special Issue The Role of Complement in Cancer Immunotherapy)

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16 pages, 866 KiB

Open AccessFeature PaperReview

Complement and Cancer—A Dysfunctional Relationship?

by Joshua M. Thurman, Jennifer Laskowski and Raphael A. Nemenoff

Antibodies 2020, 9(4), 61; https://doi.org/10.3390/antib9040061 - 5 Nov 2020

Cited by 11 | Viewed by 5507

Abstract

Although it was long believed that the complement system helps the body to identify and remove transformed cells, it is now clear that complement activation contributes to carcinogenesis and can also help tumors to escape immune-elimination. Complement is activated by several different mechanisms in various types of cancer, and complement activation fragments have multiple different downstream effects on cancer cells and throughout the tumor microenvironment. Thus, the role of complement activation in tumor biology may vary among different types of cancer and over time within a single tumor. In multiple different pre-clinical models, however, complement activation has been shown to recruit immunosuppressive myeloid cells into the tumor microenvironment. These cells, in turn, suppress anti-tumor T cell immunity, enabling the tumor to grow. Based on extensive pre-clinical work, therapeutic complement inhibitors hold great promise as a new class of immunotherapy. A greater understanding of the role of complement in tumor biology will improve our ability to identify those patients most likely to benefit from this treatment and to rationally combine complement inhibitors with other cancer therapies. Full article

(This article belongs to the Special Issue The Role of Complement in Cancer Immunotherapy)

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14 pages, 8532 KiB

Open AccessFeature PaperReview

CD46 and Oncologic Interactions: Friendly Fire against Cancer

by Michelle Elvington, M. Kathryn Liszewski and John P. Atkinson

Antibodies 2020, 9(4), 59; https://doi.org/10.3390/antib9040059 - 2 Nov 2020

Cited by 29 | Viewed by 6781

Abstract

One of the most challenging aspects of cancer therapeutics is target selection. Recently, CD46 (membrane cofactor protein; MCP) has emerged as a key player in both malignant transformation as well as in cancer treatments. Normally a regulator of complement activation, CD46 is co-expressed as four predominant isoforms on almost all cell types. CD46 is highly overexpressed on a variety of human tumor cells. Clinical and experimental data support an association between increased CD46 expression and malignant transformation and metastasizing potential. Further, CD46 is a newly discovered driver of metabolic processes and plays a role in the intracellular complement system (complosome). CD46 is also known as a pathogen magnet due to its role as a receptor for numerous microbes, including several species of measles virus and adenoviruses. Strains of these two viruses have been exploited as vectors for the therapeutic development of oncolytic agents targeting CD46. In addition, monoclonal antibody-drug conjugates against CD46 also are being clinically evaluated. As a result, there are multiple early-phase clinical trials targeting CD46 to treat a variety of cancers. Here, we review CD46 relative to these oncologic connections. Full article

(This article belongs to the Special Issue The Role of Complement in Cancer Immunotherapy)

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23 pages, 1168 KiB

Open AccessFeature PaperReview

The Role of Complement in the Mechanism of Action of Therapeutic Anti-Cancer mAbs

by Josée Golay and Ronald P. Taylor

Antibodies 2020, 9(4), 58; https://doi.org/10.3390/antib9040058 - 28 Oct 2020

Cited by 51 | Viewed by 9982

Abstract

Unconjugated anti-cancer IgG1 monoclonal antibodies (mAbs) activate antibody-dependent cellular cytotoxicity (ADCC) by natural killer (NK) cells and antibody-dependent cellular phagocytosis (ADCP) by macrophages, and these activities are thought to be important mechanisms of action for many of these mAbs in vivo. Several mAbs also activate the classical complement pathway and promote complement-dependent cytotoxicity (CDC), although with very different levels of efficacy, depending on the mAb, the target antigen, and the tumor type. Recent studies have unraveled the various structural factors that define why some IgG1 mAbs are strong mediators of CDC, whereas others are not. The role of complement activation and membrane inhibitors expressed by tumor cells, most notably CD55 and CD59, has also been quite extensively studied, but how much these affect the resistance of tumors in vivo to IgG1 therapeutic mAbs still remains incompletely understood. Recent studies have demonstrated that complement activation has multiple effects beyond target cell lysis, affecting both innate and adaptive immunity mediated by soluble complement fragments, such as C3a and C5a, and by stimulating complement receptors expressed by immune cells, including NK cells, neutrophils, macrophages, T cells, and dendritic cells. Complement activation can enhance ADCC and ADCP and may contribute to the vaccine effect of mAbs. These different aspects of complement are also briefly reviewed in the specific context of FDA-approved therapeutic anti-cancer IgG1 mAbs. Full article

(This article belongs to the Special Issue The Role of Complement in Cancer Immunotherapy)

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21 pages, 2984 KiB

Open AccessFeature PaperReview

Complement System: Promoter or Suppressor of Cancer Progression?

by Margot Revel, Marie V. Daugan, Catherine Sautés-Fridman, Wolf H. Fridman and Lubka T. Roumenina

Antibodies 2020, 9(4), 57; https://doi.org/10.3390/antib9040057 - 25 Oct 2020

Cited by 61 | Viewed by 9161

Abstract

Constituent of innate immunity, complement is present in the tumor microenvironment. The functions of complement include clearance of pathogens and maintenance of homeostasis, and as such could contribute to an anti-tumoral role in the context of certain cancers. However, multiple lines of evidence show that in many cancers, complement has pro-tumoral actions. The large number of complement molecules (over 30), the diversity of their functions (related or not to the complement cascade), and the variety of cancer types make the complement-cancer topic a very complex matter that has just started to be unraveled. With this review we highlight the context-dependent role of complement in cancer. Recent studies revealed that depending of the cancer type, complement can be pro or anti-tumoral and, even for the same type of cancer, different models presented opposite effects. We aim to clarify the current knowledge of the role of complement in human cancers and the insights from mouse models. Using our classification of human cancers based on the prognostic impact of the overexpression of complement genes, we emphasize the strong potential for therapeutic targeting the complement system in selected subgroups of cancer patients. Full article

(This article belongs to the Special Issue The Role of Complement in Cancer Immunotherapy)

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25 pages, 9449 KiB

Open AccessFeature PaperReview

How Do mAbs Make Use of Complement to Kill Cancer Cells? The Role of Ca²⁺

by Ronald P. Taylor and Margaret A. Lindorfer

Antibodies 2020, 9(3), 45; https://doi.org/10.3390/antib9030045 - 4 Sep 2020

Cited by 3 | Viewed by 4770

Abstract

We examined the kinetics and mechanisms by which monoclonal antibodies (mAbs) utilize complement to rapidly kill targeted cancer cells. Based on results from flow cytometry, confocal microscopy and high-resolution digital imaging experiments, the general patterns which have emerged reveal cytotoxic activities mediated by substantial and lethal Ca²⁺ fluxes. The Ca²⁺ fluxes are common to the reported pathways that have been utilized by other toxins in killing nucleated cells. These reactions terminate in very high levels of cell killing, and based on these considerations, we suggest additional strategies to further enhance mAb-based targeting of cancer with complement. Full article

(This article belongs to the Special Issue The Role of Complement in Cancer Immunotherapy)

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