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 Journal Article
| Authors: | Holmgaard, R. B.; Zamarin, D.; Lesokhin, A.; Merghoub, T.; Wolchok, J. D. |
| Article Title: | 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 |
| 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. © 2016 The Authors. |
| Keywords: | immunotherapy; ctla-4; pd-1; ido; mdscs; csf-1r |
| Journal Title: | EBioMedicine |
| Volume: | 6 |
| ISSN: | 2352-3964 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2016-04-01 |
| Start Page: | 50 |
| End Page: | 58 |
| Language: | English |
| DOI: | 10.1016/j.ebiom.2016.02.024 |
| PROVIDER: | scopus |
| PMCID: | PMC4856741 |
| PUBMED: | 27211548 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 June 2016 -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work