Targeting myeloid-derived suppressor cells with colony stimulating factor-1 receptor blockade can reverse immune resistance to immunotherapy in indoleamine 2,3-dioxygenase-expressing tumors

Rikke B. Holmgaard, Dmitriy Zamarin, Alexander Lesokhin, Taha Merghoub, Jedd D. Wolchok

Research output: Contribution to journalArticlepeer-review

113 Scopus citations

Abstract

Tumor indoleamine 2,3-dioxygenase (IDO) promotes immunosuppression by direct action on effector T cells and Tregs and through recruitment, expansion and activation of myeloid-derived suppressor cells (MDSCs). Targeting of MDSCs is clinically being explored as a therapeutic strategy, though optimal targeting strategies and biomarkers predictive of response are presently unknown. Maturation and tumor recruitment of MDSCs are dependent on signaling through the receptor tyrosine kinase CSF-1R on myeloid cells. Here, we show that MDSCs are the critical cell population in IDO-expressing B16 tumors in mediating accelerated tumor outgrowth and resistance to immunotherapy. Using a clinically relevant drug, we show that inhibition of CSF-1R signaling can functionally block tumor-infiltrating MDSCs and enhance anti-tumor T cell responses. Furthermore, inhibition of CSF-1R sensitizes IDO-expressing tumors to immunotherapy with T cell checkpoint blockade, and combination of CSF-1R blockade with IDO inhibitors potently elicits tumor regression. These findings provide evidence for a critical and functional role for MDSCs on the in vivo outcome of IDO-expressing tumors.

Original languageEnglish
Pages (from-to)50-58
Number of pages9
JournaleBioMedicine
Volume6
DOIs
StatePublished - 1 Apr 2016
Externally publishedYes

Keywords

  • CSF-1R
  • CTLA-4
  • IDO
  • Immunotherapy
  • MDSCs
  • PD-1

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