Staff View: An immunoregulatory role for complement receptors in Murine Models of breast cancer

An immunoregulatory role for complement receptors in Murine Models of breast cancer

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 (C5aR...

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Main Authors:	Md. Akhir, Fazrena Nadia, Mohd. Noor, Mohd. Hezmee, Leong, Keith Weng Kit, Nabizadeh, Jamileh A., Manthey, Helga D., Sonderegger, Stefan E., Fung, Jenny Nga Ting, McGirr, Crystal E., Shiels, Ian A., Mills, Paul C., Woodruff, Trent M., Rolfe, Barbara E.
Format:	Article
Published:	MDPI 2021
Subjects:	T Technology (General)
Online Access:	http://eprints.utm.my/id/eprint/96125/ http://dx.doi.org/10.3390/antib10010002
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spelling	my.utm.961252022-07-04T03:37:08Z http://eprints.utm.my/id/eprint/96125/ An immunoregulatory role for complement receptors in Murine Models of breast cancer Md. Akhir, Fazrena Nadia Mohd. Noor, Mohd. Hezmee Leong, Keith Weng Kit Nabizadeh, Jamileh A. Manthey, Helga D. Sonderegger, Stefan E. Fung, Jenny Nga Ting McGirr, Crystal E. Shiels, Ian A. Mills, Paul C. Woodruff, Trent M. Rolfe, Barbara E. T Technology (General) 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. MDPI 2021 Article PeerReviewed Md. Akhir, Fazrena Nadia and Mohd. Noor, Mohd. Hezmee and Leong, Keith Weng Kit and Nabizadeh, Jamileh A. and Manthey, Helga D. and Sonderegger, Stefan E. and Fung, Jenny Nga Ting and McGirr, Crystal E. and Shiels, Ian A. and Mills, Paul C. and Woodruff, Trent M. and Rolfe, Barbara E. (2021) An immunoregulatory role for complement receptors in Murine Models of breast cancer. Antibodies, 10 (1). pp. 1-12. ISSN 2073-4468 http://dx.doi.org/10.3390/antib10010002
institution	Universiti Teknologi Malaysia
building	UTM Library
collection	Institutional Repository
continent	Asia
country	Malaysia
content_provider	Universiti Teknologi Malaysia
content_source	UTM Institutional Repository
url_provider	http://eprints.utm.my/
topic	T Technology (General)
spellingShingle	T Technology (General) Md. Akhir, Fazrena Nadia Mohd. Noor, Mohd. Hezmee Leong, Keith Weng Kit Nabizadeh, Jamileh A. Manthey, Helga D. Sonderegger, Stefan E. Fung, Jenny Nga Ting McGirr, Crystal E. Shiels, Ian A. Mills, Paul C. Woodruff, Trent M. Rolfe, Barbara E. An immunoregulatory role for complement receptors in Murine Models of breast cancer
description	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.
format	Article
author	Md. Akhir, Fazrena Nadia Mohd. Noor, Mohd. Hezmee Leong, Keith Weng Kit Nabizadeh, Jamileh A. Manthey, Helga D. Sonderegger, Stefan E. Fung, Jenny Nga Ting McGirr, Crystal E. Shiels, Ian A. Mills, Paul C. Woodruff, Trent M. Rolfe, Barbara E.
author_facet	Md. Akhir, Fazrena Nadia Mohd. Noor, Mohd. Hezmee Leong, Keith Weng Kit Nabizadeh, Jamileh A. Manthey, Helga D. Sonderegger, Stefan E. Fung, Jenny Nga Ting McGirr, Crystal E. Shiels, Ian A. Mills, Paul C. Woodruff, Trent M. Rolfe, Barbara E.
author_sort	Md. Akhir, Fazrena Nadia
title	An immunoregulatory role for complement receptors in Murine Models of breast cancer
title_short	An immunoregulatory role for complement receptors in Murine Models of breast cancer
title_full	An immunoregulatory role for complement receptors in Murine Models of breast cancer
title_fullStr	An immunoregulatory role for complement receptors in Murine Models of breast cancer
title_full_unstemmed	An immunoregulatory role for complement receptors in Murine Models of breast cancer
title_sort	immunoregulatory role for complement receptors in murine models of breast cancer
publisher	MDPI
publishDate	2021
url	http://eprints.utm.my/id/eprint/96125/ http://dx.doi.org/10.3390/antib10010002
_version_	1738510326882631680
score	13.211869

An immunoregulatory role for complement receptors in Murine Models of breast cancer

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