Journal
EBIOMEDICINE
Volume 6, Issue -, Pages 50-58Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ebiom.2016.02.024
Keywords
Immunotherapy; IDO; MDSCs; CSF-1R; CTLA-4; PD-1
Funding
- NIH [R01CA56821]
- NIH/NCI Cancer Center Support Grant [P30CA008748]
- Swim Across America
- Ludwig Cancer Research
- Breast Cancer Research Foundation
- Danish Cancer Society [R56-A2943-12-S2]
- Carlsberg Foundation, Denmark [CF14-0224]
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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. (C) 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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