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.
authors.affiliation: Swim Across America/Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
authors.forename: Rikke B
authors.initials: RB
authors.lastname: Holmgaard
authors.affiliation: Swim Across America/Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY, United States; Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, United States; Weill Cornell Medical College, New York, NY 10065, United States; Graduate School of Medical Sciences of Cornell University, New York, NY 10065, United States.
authors.forename: Dmitriy
authors.initials: D
authors.lastname: Zamarin
authors.affiliation: Swim Across America/Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY, United States; Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, United States; Weill Cornell Medical College, New York, NY 10065, United States; Graduate School of Medical Sciences of Cornell University, New York, NY 10065, United States.
authors.forename: Alexander
authors.initials: A
authors.lastname: Lesokhin
authors.affiliation: Swim Across America/Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
authors.forename: Taha
authors.initials: T
authors.lastname: Merghoub
authors.affiliation: Swim Across America/Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY, United States; Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, United States; Weill Cornell Medical College, New York, NY 10065, United States; Graduate School of Medical Sciences of Cornell University, New York, NY 10065, United States. Electronic address: wolchokj@mskcc.org.
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
mesh_terms: D000818:Animals; D060908:CTLA-4 Antigen / Q000008:administration & dosage; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D058990:Molecular Targeted Therapy; D000072737:Myeloid-Derived Suppressor Cells / Q000187:drug effects*; D061026:Programmed Cell Death 1 Receptor / Q000008:administration & dosage; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D060908:CTLA-4 Antigen; D004791:Enzyme Inhibitors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D061026:Programmed Cell Death 1 Receptor; D016186:Receptor, Macrophage Colony-Stimulating Factor
keywords: CSF-1R; CTLA-4; IDO; Immunotherapy; MDSCs; PD-1