title: Sorafenib combined with HER-2 targeted vaccination can promote effective T cell immunity in vivo.
abstract: The tumor microenvironment (TME) is established and maintained through complex interactions between tumor cells and host stromal elements. Therefore, therapies that target multiple cellular components of the tumor may be most effective. Sorafenib, a multi-kinase inhibitor, alters signaling pathways in both tumor cells and host stromal cells. Thus, we explored the potential immune-modulating effects of sorafenib in a murine HER-2-(neu) overexpressing breast tumor model alone and in combination with a HER-2 targeted granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting vaccine (3T3neuGM). In vitro, sorafenib inhibited the growth of HER-2 overexpressing NT2.5 tumor cells, inducing apoptosis. Sorafenib also interfered with ERK MAPK, p38 MAPK, and STAT3 signaling, as well as cyclin D expression, but did not affect HER-2 or AKT signaling. In vivo, single agent sorafenib disrupted the tumor-associated vasculature and induced tumor cell apoptosis, effectively inducing the regression of established NT2.5 tumors in immune competent FVB/N mice. Immune depletion studies demonstrated that both CD4+and CD8+T cells were required for tumor regression. Sorafenib treatment did not impact the rate of tumor clearance induced by vaccination with 3T3neuGM in tumor-bearing FVB/N mice relative to either sorafenib treatment or vaccination alone. In vivo studies further demonstrated that sorafenib enhanced the accumulation of both CD4+and CD8+T cells into the TME of vaccinated mice. Together, these findings suggest that GM-CSF-secreting cellular immunotherapy may be integrated with sorafenib without impairing vaccine-based immune responses.
authors.affiliation: Johns Hopkins University School of Medicine, Department of Oncology, Baltimore, MD 21287, USA; Johns Hopkins University School of Medicine, Graduate Program in Pathobiology, Baltimore, MD 21287, USA.
authors.forename: Melek M E
authors.initials: MM
authors.lastname: Sunay
authors.affiliation: Johns Hopkins University School of Medicine, Department of Oncology, Baltimore, MD 21287, USA; Department of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Jeremy B
authors.initials: JB
authors.lastname: Foote
authors.affiliation: Johns Hopkins University School of Medicine, Department of Oncology, Baltimore, MD 21287, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Leatherman
authors.affiliation: Johns Hopkins University School of Medicine, Department of Oncology, Baltimore, MD 21287, USA.
authors.forename: Justin P
authors.initials: JP
authors.lastname: Edwards
authors.affiliation: Johns Hopkins University School of Medicine, Department of Oncology, Baltimore, MD 21287, USA.
authors.forename: Todd D
authors.initials: TD
authors.lastname: Armstrong
authors.affiliation: Johns Hopkins University School of Medicine, Department of Oncology, Baltimore, MD 21287, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Nirschl
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Hicks
authors.affiliation: Johns Hopkins University School of Medicine, Department of Oncology, Baltimore, MD 21287, USA; Johns Hopkins University School of Medicine, Graduate Program in Pathobiology, Baltimore, MD 21287, USA. Electronic address: emensle@jhmi.edu.
authors.forename: Leisha A
authors.initials: LA
authors.lastname: Emens
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000276:immunology / Q000628:therapy*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation*; D019496:Cancer Vaccines / Q000276:immunology*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D003131:Combined Modality Therapy; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000627:therapeutic use; D006801:Humans; D007111:Immunity, Cellular; D016219:Immunotherapy, Adoptive / Q000379:methods*; D051379:Mice; D008815:Mice, Inbred Strains; D009374:Neoplasms, Experimental; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D047368:Tumor Burden; D059016:Tumor Microenvironment
chemical_list: D019496:Cancer Vaccines; D048049:Extracellular Signal-Regulated MAP Kinases; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D009536:Niacinamide; D010671:Phenylurea Compounds; D018719:Erb-b2 Receptor Tyrosine Kinases; D000077157:Sorafenib
keywords: Breast cancer; Immunity; Immunotherapy; Sorafenib; Vaccine