A novel role of hematopoietic CCL5 in promoting triple-negative mammary tumor progression by regulating generation of myeloid-derived suppressor cells

Zhang, Y.; Lv, D. D.; Kurt, Robert A.; Bu, W.; Kim, H. J.; Li, Y.; Ma, X. J.

A novel role of hematopoietic CCL5 in promoting triple-negative mammary tumor progression by regulating generation of myeloid-derived suppressor cells

Abstract

CCL5 is a member of the CC chemokine family expressed in a wide array of immune and non-immune cells in response to stress signals. CCL5 expression correlates with advanced human breast cancer. However, its functional significance and mode of action have not been established. Here, we show that CCL5-deficient mice are resistant to highly aggressive, triple-negative mammary tumor growth. Hematopoietic CCL5 is dominant in this phenotype. The absence of hematopoietic CCL5 causes aberrant generation of CD11b(+)/Gr-1(+), myeloid-derived suppressor cells (MDSCs) in the bone marrow in response to tumor growth by accumulating Ly6C(hi) and Ly6G(+) MDSCs with impaired capacity to suppress cytotoxicity of CD8(+) T cells. These properties of CCL5 are observed in both orthotopic and spontaneous mammary tumors. Antibody-mediated systemic blockade of CCL5 inhibits tumor progression and enhances the efficacy of therapeutic vaccination against non-immunogenic tumors. CCL5 also helps maintain the immunosuppressive capacity of human MDSCs. Our study uncovers a novel, chemokine-independent activity of the hematopoietically derived CCL5 that promotes mammary tumor progression via generating MDSCs in the bone marrow in cooperation with tumor-derived colony-stimulating factors. The study sheds considerable light on the interplay between the hematopoietic compartment and tumor niche. Because of the apparent dispensable nature of this molecule in normal physiology, CCL5 may represent an excellent therapeutic target in immunotherapy for breast cancer as well as a broad range of solid tumors that have significant amounts of MDSC infiltration.

Title	A novel role of hematopoietic CCL5 in promoting triple-negative mammary tumor progression by regulating generation of myeloid-derived suppressor cells
Creator	Zhang, Y.
	Lv, D. D.
	Kurt, Robert A.
	Bu, W.
	Kim, H. J.
	Li, Y.
	Ma, X. J.
Publisher	Cell Research
Academic Department	Biology
Division	Natural Sciences
Organization	Lafayette College
Date Issued	March 2013
Date Available	2023-03-29
Type	Article
Language	English
Keyword	CCL5
	mammary tumor
	myeloid-derived suppressor cell
	cytotoxic T lymphocyte
	bone marrow
	immune response
	triple-negative breast cancer
Bibliographic Citation	Zhang, Y. (2013 Mar) "A novel role of hematopoietic CCL5 in promoting triple-negative mammary tumor progression by regulating generation of myeloid-derived suppressor cells." Cell Research 23 (3): 394-408.
Standard Identifier	Handle 10385/1r66j263f
Standard Identifier	DOI 10.1038/cr.2012.178
Permalink	http://hdl.handle.net/10385/1r66j263f
Rights Statement	In Copyright
Rights Holders	IBCB
	CAS
	SIBS