Targeting autocrine CCL5-CCR5 axis reprograms immunosuppressive myeloid cells and reinvigorates antitumor immunity

Yi Ban, Junhua Mai, Xin Li, Marisa Mitchell-Flack, Tuo Zhang, Lixing Zhang, Lotfi Chouchane, Mauro Ferrari, Haifa Shen, Xiaojing Ma

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32 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2857-2868
Number of pages12
JournalCancer Research
Volume77
Issue number11
DOIs
Publication statusPublished - 1 Jun 2017

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Ban, Y., Mai, J., Li, X., Mitchell-Flack, M., Zhang, T., Zhang, L., Chouchane, L., Ferrari, M., Shen, H., & Ma, X. (2017). Targeting autocrine CCL5-CCR5 axis reprograms immunosuppressive myeloid cells and reinvigorates antitumor immunity. Cancer Research, 77(11), 2857-2868. https://doi.org/10.1158/0008-5472.CAN-16-2913