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• W2023555713 abstract "You have accessJournal of UrologyKidney Cancer: Basic Research III1 Apr 2015PD33-08 PAZOPANIB, SUNITINIB, AND AXITINIB REDUCE EXPANSION OF IN VITRO INDUCED SUPPRESSIVE MACROPHAGES Raman Unnikrishnan, Patricia Rayman, Yu Yang, Claudia Marcela Diaz-Montero, and James Finke Raman UnnikrishnanRaman Unnikrishnan More articles by this author , Patricia RaymanPatricia Rayman More articles by this author , Yu YangYu Yang More articles by this author , Claudia Marcela Diaz-MonteroClaudia Marcela Diaz-Montero More articles by this author , and James FinkeJames Finke More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.2106AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Tyrosine kinase inhibitors (TKIs) are the first line treatment for metastatic renal cell carcinoma (RCC). They are felt to be immunomodulatory. Tumor associated macrophages are pro-angiogenic and immunosuppressive cells found within tumors. We hypothesized that the TKIs sunitinib, pazopanib, and axitinib could reduce the expansion of these suppressive macrophages. We thus aimed to expand suppressive macrophages in vitro using a combination of granulocyte macrophage colony stimulating factor (GM-CSF) and interleukin-6 (IL-6) and examined the effect of the TKIs on their expansion. We then searched for this same population of cells in vivo within RCC tumors. METHODS Normal peripheral blood mononuclear cells were isolated from healthy donors and cultured with GM-CSF and IL-6 for 7 days in the presence and absence of either sunitinib, pazopanib, or axitinib at three concentrations: subphysiologic (0.1X), physiologic (1X), and supraphysiologic dose (10X). Cells with a suppressive macrophage phenotype (HLA-DR/CD33/CD14) were counted at Day 0 and Day 7. They were then isolated and recultured with autologous stimulated T-cells for 3 days. Intracellular T-cell IFN-gamma levels were then measured to evaluate the level of T-cell suppression. Flow cytometry of digested RCC tumors were analyzed for evidence of HLA-DR/CD33/CD14 cells. RESULTS Induced cells were confirmed to be macrophages on microscopy and flow cytometry. They were suppressive as they blocked autologous T-cell IFN-gamma production. All three TKIs reduced expansion of the cells, but the most pronounced effect was seen with pazopanib (see Figure). Relative to suppressive cells cultured with no drug, only 36% expanded with pazopanib at 0.1X dose, 27% at 1X dose, and 13% at 10X dose. This same population of cells (HLA-DR/CD33/CD14) was found on flow cytometry in digested RCC tumors (12.4%; n=26). CONCLUSIONS The combination of GM-CSF/IL-6 induced the expansion of suppressive macrophages in vitro. This same population was found in RCC tumors. The addition of sunitinib, axitinib, or pazopanib reduced their expansion, with the most profound effect from pazopanib. This suggests TKIs may block the expansion of suppressive macrophages in vivo, improving the antitumor immune response, and supports that TKIs show promise for use with future immunotherapy. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e712 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.Metrics Author Information Raman Unnikrishnan More articles by this author Patricia Rayman More articles by this author Yu Yang More articles by this author Claudia Marcela Diaz-Montero More articles by this author James Finke More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ..." @default.
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