title: Direct and differential suppression of myeloid-derived suppressor cell subsets by sunitinib is compartmentally constrained.
abstract: The antiangiogenic drug sunitinib is a receptor tyrosine kinase inhibitor with significant, yet not curative, therapeutic effects in metastatic renal cell carcinoma (RCC). Sunitinib is also an immunomodulator, potently reversing myeloid-derived suppressor cell (MDSC) accumulation and T-cell inhibition in the blood even of nonresponder RCC patients. We observed that sunitinib similarly prevented MDSC accumulation and restored normal T-cell function to the spleens of tumor-bearing mice, independent of the capacity of sunitinib to inhibit tumor progression (RENCA>CT26>4T1). Both monocytic and neutrophilic splenic MDSC were highly repressible by sunitinib. In contrast, MDSC within the microenvironment of 4T1 tumors or human RCC tumors proved highly resistant to sunitinib and ambient T-cell function remained suppressed. Proteomic analyses comparing tumor to peripheral compartments showed that granulocyte macrophage colony-stimulating factor (GM-CSF) predicted sunitinib resistance and recombinant GM-CSF conferred sunitinib resistance to MDSC in vivo and in vitro. MDSC conditioning with GM-CSF uniquely inhibited signal transducers and activators of transcription (STAT3) and promoted STAT5 activation. STAT5ab(null/null) MDSC were rendered sensitive to sunitinib in the presence of GM-CSF in vitro. We conclude that compartment-dependent GM-CSF exposure in resistant tumors may account for the regionalized effect of sunitinib upon host MDSC modulation and hypothesize that ancillary strategies to decrease such regionalized escape will enhance the potency of sunitinib as an immunomodulator and a cancer therapy.
authors.affiliation: Department of Immunology, Taussig Cancer Institute, and Glickman Urological Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Ko
authors.forename: Patricia
authors.initials: P
authors.lastname: Rayman
authors.forename: Joanna
authors.initials: J
authors.lastname: Ireland
authors.forename: Shadi
authors.initials: S
authors.lastname: Swaidani
authors.forename: Geqiang
authors.initials: G
authors.lastname: Li
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Bunting
authors.forename: Brian
authors.initials: B
authors.lastname: Rini
authors.forename: James H
authors.initials: JH
authors.lastname: Finke
authors.forename: Peter A
authors.initials: PA
authors.lastname: Cohen
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000276:immunology*; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D022423:Myeloid Cells / Q000187:drug effects* / Q000276:immunology; D011758:Pyrroles / Q000494:pharmacology*; D000077210:Sunitinib; D013491:Suppressor Factors, Immunologic / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology
chemical_list: D039481:CD11b Antigen; D007155:Immunologic Factors; D007211:Indoles; D011758:Pyrroles; D013491:Suppressor Factors, Immunologic; D000077210:Sunitinib
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