Tumor-promoting effects of myeloid-derived suppressor cells are potentiated by hypoxia-induced expression of miR-210

Muhammad Zaeem Noman, Bassam Janji, Shijun Hu, Joseph C. Wu, Fabio Martelli, Vincenzo Bronte, Salem Chouaib

Research output: Contribution to journalArticle

Abstract

Myeloid-derived suppressor cells (MDSC) contribute significantly to the malignant characters conferred by hypoxic tumor microenvironments. However, selective biomarkers of MDSC function in this critical setting have not been defined. Here, we report that miR-210 expression is elevated by hypoxia-inducible factor-1a (HIF1α) in MDSC localized to tumors, compared with splenic MDSC from tumor-bearing mice. In tumor MDSC, we determined that HIF1α was bound directly to a transcriptionally active hypoxia-response element in the miR-210 proximal promoter. miR-210 overexpression was sufficient to enhance MDSC-mediated T-cell suppression under normoxic conditions, while targeting hypoxia-induced miR-210 was sufficient to decrease MDSC function against T cells. Mechanistic investigations revealed that miR-210 modulated MDSC function by increasing arginase activity and nitric oxide production, without affecting reactive oxygen species, IL6, or IL10 production or expression of PD-L1. In splenic MDSC, miR-210 regulated Arg1, Cxcl12, and IL16 at the levels of both mRNA and protein, the reversal of which under normoxic conditions decreased T-cell-suppressive effects and IFNγ production. Interestingly, miR-210 overexpression or targeting IL16 or CXCL12 enhanced the immunosuppressive activity of MDSC in vivo, resulting in increased tumor growth. Taken together, these results provide a preclinical rationale to explore miR-210 inhibitory oligonucleotides as adjuvants to boost immunotherapeutic responses in cancer patients.

Original languageEnglish
Pages (from-to)3771-3787
Number of pages17
JournalCancer Research
Volume75
Issue number18
DOIs
Publication statusPublished - Sep 15 2015

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Cell Hypoxia
Neoplasms
Interleukin-16
T-Lymphocytes
Myeloid-Derived Suppressor Cells
Arginase
Tumor Microenvironment
Response Elements
Immunosuppressive Agents
Oligonucleotides
Interleukin-10
Interleukin-6
Reactive Oxygen Species
Nitric Oxide
Biomarkers

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Tumor-promoting effects of myeloid-derived suppressor cells are potentiated by hypoxia-induced expression of miR-210. / Noman, Muhammad Zaeem; Janji, Bassam; Hu, Shijun; Wu, Joseph C.; Martelli, Fabio; Bronte, Vincenzo; Chouaib, Salem.

In: Cancer Research, Vol. 75, No. 18, 15.09.2015, p. 3771-3787.

Research output: Contribution to journalArticle

Noman, Muhammad Zaeem ; Janji, Bassam ; Hu, Shijun ; Wu, Joseph C. ; Martelli, Fabio ; Bronte, Vincenzo ; Chouaib, Salem. / Tumor-promoting effects of myeloid-derived suppressor cells are potentiated by hypoxia-induced expression of miR-210. In: Cancer Research. 2015 ; Vol. 75, No. 18. pp. 3771-3787.
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