Title | Targeting Autocrine CCL5-CCR5 Axis Reprograms Immunosuppressive Myeloid Cells and Reinvigorates Antitumor Immunity. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Ban Y, Mai J, Li X, Mitchell-Flack M, Zhang T, Zhang L, Chouchane L, Ferrari M, Shen H, Ma X |
Journal | Cancer Res |
Volume | 77 |
Issue | 11 |
Pagination | 2857-2868 |
Date Published | 2017 06 01 |
ISSN | 1538-7445 |
Keywords | Animals, 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. . |
DOI | 10.1158/0008-5472.CAN-16-2913 |
Alternate Journal | Cancer Res |
PubMed ID | 28416485 |
PubMed Central ID | PMC5484057 |
Grant List | R01 CA193880 / CA / NCI NIH HHS / United States T32 AI007621 / AI / NIAID NIH HHS / United States U54 CA210181 / CA / NCI NIH HHS / United States |
Submitted by wcm_microbiolog... on October 13, 2020 - 1:43pm