کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2120664 | 1546893 | 2016 | 9 صفحه PDF | دانلود رایگان |
• Tumor-infiltrating MDSCs promote accelerated outgrowth of IDO-expressing tumors.
• MDSCs infiltrating IDO-expressing tumors mediate resistance to immunotherapy.
• Combination of CSF-1R blockade with IDO inhibitors potently elicits tumor regression.
• CSF-1R blockade sensitizes tumors to the effects of immune checkpoint blockade.Our data demonstrate that therapy with CSF-1R-blocking agents offers therapeutic benefit as a single agent and potentiates the effect of immunotherapeutic agents in IDO-expressing tumors infiltrated with CSF-1R-expressing MDSCs. These findings provide important insights into basic mechanisms underlying IDO mediated immune suppression and resistance to immunotherapies. In addition, it provides a strong rationale for therapeutic combinations with CSF-1R inhibitors in tumors expressing elevated IDO and highly infiltrated with MDSCs as predictive biomarkers.
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.
Journal: EBioMedicine - Volume 6, April 2016, Pages 50–58