title: Tumor-associated GM-CSF overexpression induces immunoinhibitory molecules via STAT3 in myeloid-suppressor cells infiltrating liver metastases.
abstract: Assumptions that liver immune cells and immunosuppressive pathways are similar to their counterparts in other spaces have led to gaps in our understanding of intrahepatic neoplasm aggressiveness. Myeloid-derived suppressor cells (MDSCs) are potent inhibitors of antitumor immunity and pose a major obstacle to solid tumor treatment. Liver MDSCs (L-MDSCs) associated with liver metastases (LM) are particularly problematic by contributing to intrahepatic immunosuppression that promotes tumor progression. L-MDSCs have been reported to expand in response to granulocyte-macrophages colony-stimulating factor (GM-CSF) and suppress antitumor immunity in LM. To extend these findings, we examined mechanisms of intrahepatic immunosuppression exploited by L-MDSCs. We found that the majority of L-MDSCs co-expressed GM-CSF receptor (GM-CSF-R), indoleamine 2,3-dioxygenase (IDO) and programmed death ligand 1 (PD-L1), while demonstrating high levels of signal transducer and activator of transcription factor 3 (STAT3) activation. GM-CSF-secreting tumor cells induced STAT3 phosphorylation in L-MDSCs in addition to expression of IDO and PD-L1. GM-CSF or GM-CSF-R blockade markedly reduced L-MDSC IDO and PD-L1 expression, implicating tumor-derived GM-CSF in supporting L-MDSC-immunoinhibitory molecule expression. Small-molecule inhibitors of Janus-activated kinase 2 (JAK2) and STAT3 also dramatically diminished IDO and PD-L1 expression in L-MDSCs. We determined that STAT3 exerts transcriptional control over L-MDSC IDO and PD-L1 expression by binding to the IDO1 and PD-L1 promoters. Our data suggest that the GM-CSF/JAK2/STAT3 axis in L-MDSCs drives immunosuppression in a model of LM and blockade of this pathway may enable rescue of intrahepatic antitumor immunity.
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Roger Williams Medical Center, Providence, RI, USA.
authors.forename: M
authors.initials: M
authors.lastname: Thorn
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Roger Williams Medical Center, Providence, RI, USA.
authors.forename: P
authors.initials: P
authors.lastname: Guha
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Roger Williams Medical Center, Providence, RI, USA.
authors.forename: M
authors.initials: M
authors.lastname: Cunetta
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Roger Williams Medical Center, Providence, RI, USA.|Department of Surgery, Boston University School of Medicine, Boston, MA, USA.
authors.forename: N J
authors.initials: NJ
authors.lastname: Espat
authors.affiliation: Department of Surgery and Cell Biology, New York University School of Medicine, New York, NY, USA.
authors.forename: G
authors.initials: G
authors.lastname: Miller
authors.affiliation: Department of Medicine, Tufts University School of Medicine, Boston, MA, USA.
authors.forename: R P
authors.initials: RP
authors.lastname: Junghans
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Roger Williams Medical Center, Providence, RI, USA.|Department of Surgery, Boston University School of Medicine, Boston, MA, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Katz
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000235:genetics / Q000378:metabolism; D015415:Biomarkers; D004195:Disease Models, Animal; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics*; D056747:Immunomodulation / Q000235:genetics*; D016130:Immunophenotyping; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics* / Q000276:immunology / Q000378:metabolism* / Q000556:secondary; D008297:Male; D051379:Mice; D008954:Models, Biological; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D060890:B7-H1 Antigen; D015415:Biomarkers; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D050796:STAT3 Transcription Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor