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Cancer Res. 2017 Jun 1;77(11):2857-2868. doi: 10.1158/0008-5472.CAN-16-2913. Epub 2017 Apr 17.

Targeting Autocrine CCL5-CCR5 Axis Reprograms Immunosuppressive Myeloid Cells and Reinvigorates Antitumor Immunity.

Author information

1
Department of Microbiology and Immunology, Weill Cornell Medicine, New York, New York.
2
Department of NanoMedicine, Houston Methodist Research Institute, Houston, Texas.
3
Hunan Clinical Meditech Research Center for Breast Cancer, Xiangya Hospital, Central South University, Changsha, Hunan, China.
4
Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, New York.
5
Laboratory of Genetic Medicine and Immunology, Weill Cornell Medical College in Qatar, Doha, Qatar.
6
Department of Medicine, Weill Cornell Medicine, New York, New York.
7
Department of Microbiology and Immunology, Weill Cornell Medicine, New York, New York. xim2002@med.cornell.edu.
8
Key Laboratory of Systems Biomedicine, Ministry of Education, Shanghai Center for Systems Biomedicine, Sheng Yushou Center of Cell Biology and Immunology, School of Life Science and Biotechnology, Shanghai Jiaotong University, Shanghai, China.

Abstract

The tumor-promoting potential of CCL5 has been proposed but remains poorly understood. We demonstrate here that an autocrine CCL5-CCR5 axis is a major regulator of immunosuppressive myeloid cells (IMC) of both monocytic and granulocytic lineages. The absence of the autocrine CCL5 abrogated the generation of granulocytic myeloid-derived suppressor cells and tumor-associated macrophages. In parallel, enhanced maturation of intratumoral neutrophils and macrophages occurred in spite of tumor-derived CCL5. The refractory nature of ccl5-null myeloid precursors to tumor-derived CCL5 was attributable to their persistent lack of membrane-bound CCR5. The changes in the ccl5-null myeloid compartment subsequently resulted in increased tumor-infiltrating cytotoxic CD8+ T cells and decreased regulatory T cells in tumor-draining lymph nodes. An analysis of human triple-negative breast cancer specimens demonstrated an inverse correlation between "immune CCR5" levels and the maturation status of tumor-infiltrating neutrophils as well as 5-year-survival rates. Targeting the host CCL5 in bone marrow via nanoparticle-delivered expression silencing, in combination with the CCR5 inhibitor Maraviroc, resulted in strong reductions of IMC and robust antitumor immunities. Our study suggests that the myeloid CCL5-CCR5 axis is an excellent target for cancer immunotherapy. Cancer Res; 77(11); 2857-68. ©2017 AACR.

PMID:
28416485
PMCID:
PMC5484057
DOI:
10.1158/0008-5472.CAN-16-2913
[Indexed for MEDLINE]
Free PMC Article

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