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

TitleTargeting Autocrine CCL5-CCR5 Axis Reprograms Immunosuppressive Myeloid Cells and Reinvigorates Antitumor Immunity.
Publication TypeJournal Article
Year of Publication2017
AuthorsBan Y, Mai J, Li X, Mitchell-Flack M, Zhang T, Zhang L, Chouchane L, Ferrari M, Shen H, Ma X
JournalCancer Res
Volume77
Issue11
Pagination2857-2868
Date Published2017 06 01
ISSN1538-7445
KeywordsAnimals, Autocrine Communication, Breast Neoplasms, Cell Line, Tumor, Chemokine CCL5, Disease Models, Animal, Female, Humans, Immunosuppressive Agents, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Myeloid Cells
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 -null myeloid precursors to tumor-derived CCL5 was attributable to their persistent lack of membrane-bound CCR5. The changes in the -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. .

DOI10.1158/0008-5472.CAN-16-2913
Alternate JournalCancer Res
PubMed ID28416485
PubMed Central IDPMC5484057
Grant ListR01 CA193880 / CA / NCI NIH HHS / United States
T32 AI007621 / AI / NIAID NIH HHS / United States
U54 CA210181 / CA / NCI NIH HHS / United States

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