title: Sunitinib facilitates the activation and recruitment of therapeutic anti-tumor immunity in concert with specific vaccination.
abstract: The multikinase inhibitor sunitinib malate (SUT) has been reported to reduce levels of myeloid suppressor cells and Treg cells in cancer patients, hypothetically diminishing intrinsic impediments for active immunization against tumor-associated antigens in such individuals. The goal of this study was to identify longitudinal immune molecular and cellular changes associated with tumor regression and disease-free status after the treatment of established day 7 s.c. MO5 (B16.OVA) melanomas with SUT alone (1 mg/day via oral gavage for 7 days), vaccination using ovalbumin (OVA) peptide-pulsed dendritic cell [vaccine (VAC)] alone, or the combination of SUT and VAC (SUT/VAC). We observed superior anti-tumor efficacy for SUT/VAC combination approaches, particularly when SUT was applied at the time of the initial vaccination or the VAC boost. Treatment effectiveness was associated with the acute loss of (and/or failure to recruit) cells bearing myeloid-derived suppressor cells or Treg phenotypes within the tumor microenvironment (TME) and the corollary, prolonged enhancement of Type-1 anti-OVA CD8(+) T cell responses in the tumor-draining lymph node and the TME. Enhanced Type-1 T cell infiltration of tumors was associated with treatment-induced expression of vascular cell adhesion molecule-1 (VCAM-1) and CXCR3 ligand chemokines in vascular/peri-vascular cells within the TME, with SUT/VAC therapy benefits conditionally negated upon adminsitration of CXCR3 or VCAM-1 blocking antibodies. These data support the ability of a short 7 day course of SUT to (re)condition the TME to become more receptive to the recruitment and prolonged therapeutic action of (VAC-induced) anti-tumor Tc1 cells.
authors.affiliation: Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Anamika
authors.initials: A
authors.lastname: Bose
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Taylor
authors.forename: Sean
authors.initials: S
authors.lastname: Alber
authors.forename: Simon C
authors.initials: SC
authors.lastname: Watkins
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Garcia
authors.forename: Brian I
authors.initials: BI
authors.lastname: Rini
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Ko
authors.forename: Peter A
authors.initials: PA
authors.lastname: Cohen
authors.forename: James H
authors.initials: JH
authors.lastname: Finke
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Storkus
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D003713:Dendritic Cells / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D016219:Immunotherapy, Adoptive; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D008198:Lymph Nodes / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology* / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology*; D054367:Receptors, CXCR3 / Q000276:immunology; D000077210:Sunitinib; D013601:T-Lymphocytes / Q000276:immunology; D059016:Tumor Microenvironment / Q000276:immunology; D019010:Vascular Cell Adhesion Molecule-1 / Q000276:immunology
chemical_list: D019138:Antibodies, Blocking; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D007211:Indoles; D011758:Pyrroles; D054367:Receptors, CXCR3; D019010:Vascular Cell Adhesion Molecule-1; D000077210:Sunitinib