title: Myeloid-derived suppressor cells adhere to physiologic STAT3- vs STAT5-dependent hematopoietic programming, establishing diverse tumor-mediated mechanisms of immunologic escape.
abstract: The receptor tyrosine kinase inhibitor, sunitinib, is astonishingly effective in its capacity to reduce MDSCs in peripheral tissues such as blood (human) and spleen (mouse), restoring responsiveness of bystander T lymphocytes to TcR stimulation. Sunitinib blocks proliferation of undifferentiated MDSCs and decreases survival of more differentiated neutrophilic MDSC (n-MDSC) progeny. Ironically, sunitinib's profound effects are observed even in a total absence of detectable anti-tumor therapeutic response. This is best explained by the presence of disparate MDSC-conditioning stimuli within individual body compartments, allowing sensitivity and resistance to sunitinib to coexist within the same mouse or patient. The presence or absence of GM-CSF is likely the major determinant in each compartment, given that GM-CSF's capacity to preempt STAT3-dependent with dominant STAT5-dependent hematopoietic programming confers sunitinib resistance and redirects differentiation from the n-MDSC lineage to the more versatile monocytoid (m-MDSC) lineage. The clinical sunitinib experience underscores that strategies for MDSC and Treg depletions must be mindful of disparities among body compartments to avoid sanctuary effects. Ironically, m-MDSCs manifesting resistance to sunitinib also have the greatest potential to differentiate into tumoricidal accessory cells, by virtue of their capacity to respond to T cell-secreted IFN-γ or to TLR agonists with nitric oxide and peroxynitrate production.
authors.affiliation: Division of Hematology/Oncology, Mayo Clinic in Arizona, Scottsdale, Arizona 85258, USA. cohenpeter@mayo.edu
authors.forename: Peter A
authors.initials: PA
authors.lastname: Cohen
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Ko
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Storkus
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Spencer
authors.forename: Judy M
authors.initials: JM
authors.lastname: Bradley
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Gorman
authors.forename: Dustin B
authors.initials: DB
authors.lastname: McCurry
authors.forename: Soroya
authors.initials: S
authors.lastname: Zorro-Manrique
authors.forename: Anna Lucia
authors.initials: AL
authors.lastname: Dominguez
authors.forename: Latha B
authors.initials: LB
authors.lastname: Pathangey
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Rayman
authors.forename: Brian I
authors.initials: BI
authors.lastname: Rini
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Gendler
authors.forename: James H
authors.initials: JH
authors.lastname: Finke
mesh_terms: D000818:Animals; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D023461:Myeloid Progenitor Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology* / Q000628:therapy*; D009928:Organ Specificity; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D000077210:Sunitinib; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D019139:Tumor Escape
chemical_list: D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D000077210:Sunitinib