Mesenchymal stem cells induce PD-L1 expression through the secretion of CCL5 in breast cancer cells.

Aboulkheyr Es, H; Bigdeli, B; Zhand, S; Aref, AR; Thiery, JP; Warkiani, ME

Mesenchymal stem cells induce PD-L1 expression through the secretion of CCL5 in breast cancer cells.

Aboulkheyr Es, H Bigdeli, B Zhand, S Aref, AR Thiery, JP Warkiani, ME

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Publisher:: Wiley
Publication Type:: Journal Article
Citation:: Journal of Cellular Physiology, 2020, 236, (5), pp. 3918-3928
Issue Date:: 2020-11-04

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Field	Value	Language
dc.contributor.author	Aboulkheyr Es, H
dc.contributor.author	Bigdeli, B
dc.contributor.author	Zhand, S
dc.contributor.author	Aref, AR
dc.contributor.author	Thiery, JP
dc.contributor.author	Warkiani, ME
dc.date.accessioned	2021-03-01T21:00:59Z
dc.date.available	2020-10-21
dc.date.available	2021-03-01T21:00:59Z
dc.date.issued	2020-11-04
dc.identifier.citation	Journal of Cellular Physiology, 2020, 236, (5), pp. 3918-3928
dc.identifier.issn	0021-9541
dc.identifier.issn	1097-4652
dc.identifier.uri	http://hdl.handle.net/10453/146587
dc.description.abstract	Various factors in the tumor microenvironment (TME) regulate the expression of PD-L1 in cancer cells. In TME, mesenchymal stem cells (MSCs) play a crucial role in tumor progression, metastasis, and drug resistance. Emerging evidence suggests that MSCs can modulate the immune-suppression capacity of TME through the stimulation of PD-L1 expression in various cancers; nonetheless, their role in the induction of PD-L1 in breast cancer remained elusive. Here, we assessed the potential of MSCs in the stimulation of PD-L1 expression in a low PD-L1 breast cancer cell line and explored its associated cytokine. We assessed the expression of MSCs-related genes and their correlation with PD-L1 across 1826 breast cancer patients from the METABRIC cohort. After culturing an ER+/differentiated/low PD-L1 breast cancer cells with MSCs conditioned-medium (MSC-CM) in a microfluidic device, a variety of in-vitro assays was carried out to determine the role of MSC-CM in breast cancer cells' phenotype plasticity, invasion, and its effects on induction of PD-L1 expression. In-silico analysis showed a positive association between MSCs-related genes and PD-L1 expression in various types of breast cancer. Through functional assays, we revealed that MSC-CM not only prompts a phenotype switch but also stimulates PD-L1 expression at the protein level through secretion of various cytokines, especially CCL5. Treatment of MSCs with cytokine inhibitor pirfenidone showed a significant reduction in the secretion of CCL5 and consequently, expression of PD-L1 in breast cancer cells. We concluded that MSCs-derived CCL5 may act as a PD-L1 stimulator in breast cancer.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	Wiley
dc.relation	http://purl.org/au-research/grants/nhmrc/1143377
dc.relation.ispartof	Journal of Cellular Physiology
dc.relation.isbasedon	10.1002/jcp.30135
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	0601 Biochemistry and Cell Biology, 1116 Medical Physiology
dc.subject.classification	Biochemistry & Molecular Biology
dc.title	Mesenchymal stem cells induce PD-L1 expression through the secretion of CCL5 in breast cancer cells.
dc.type	Journal Article
utslib.citation.volume	236
utslib.location.activity	United States
utslib.for	0601 Biochemistry and Cell Biology
utslib.for	1116 Medical Physiology
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
pubs.organisational-group	/University of Technology Sydney/Strength - IBMD - Initiative for Biomedical Devices
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology/School of Biomedical Engineering
pubs.organisational-group	/University of Technology Sydney
utslib.copyright.status	closed_access	*
pubs.consider-herdc	false
dc.date.updated	2021-03-01T21:00:57Z
pubs.issue	5
pubs.publication-status	Published
pubs.volume	236
utslib.citation.issue	5

Abstract:

Various factors in the tumor microenvironment (TME) regulate the expression of PD-L1 in cancer cells. In TME, mesenchymal stem cells (MSCs) play a crucial role in tumor progression, metastasis, and drug resistance. Emerging evidence suggests that MSCs can modulate the immune-suppression capacity of TME through the stimulation of PD-L1 expression in various cancers; nonetheless, their role in the induction of PD-L1 in breast cancer remained elusive. Here, we assessed the potential of MSCs in the stimulation of PD-L1 expression in a low PD-L1 breast cancer cell line and explored its associated cytokine. We assessed the expression of MSCs-related genes and their correlation with PD-L1 across 1826 breast cancer patients from the METABRIC cohort. After culturing an ER+/differentiated/low PD-L1 breast cancer cells with MSCs conditioned-medium (MSC-CM) in a microfluidic device, a variety of in-vitro assays was carried out to determine the role of MSC-CM in breast cancer cells' phenotype plasticity, invasion, and its effects on induction of PD-L1 expression. In-silico analysis showed a positive association between MSCs-related genes and PD-L1 expression in various types of breast cancer. Through functional assays, we revealed that MSC-CM not only prompts a phenotype switch but also stimulates PD-L1 expression at the protein level through secretion of various cytokines, especially CCL5. Treatment of MSCs with cytokine inhibitor pirfenidone showed a significant reduction in the secretion of CCL5 and consequently, expression of PD-L1 in breast cancer cells. We concluded that MSCs-derived CCL5 may act as a PD-L1 stimulator in breast cancer.

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http://hdl.handle.net/10453/146587