311 ELUCIDATING MECHANISMS OF SUNITINIB RESISTANCE IN METASTATIC RENAL CELL CARCINOMA BY STUDYING ITS EFFECT ON MYELOID DERIVED SUPPRESSOR CELLS (MDSC) IN MURINE TUMOR MODELS

Abstract

You have accessJournal of UrologyKidney Cancer: Basic Research II1 Apr 2012311 ELUCIDATING MECHANISMS OF SUNITINIB RESISTANCE IN METASTATIC RENAL CELL CARCINOMA BY STUDYING ITS EFFECT ON MYELOID DERIVED SUPPRESSOR CELLS (MDSC) IN MURINE TUMOR MODELS Kevin Chandler, Charles Tannenbaum, and James Finke Kevin ChandlerKevin Chandler Cleveland, OH More articles by this author , Charles TannenbaumCharles Tannenbaum Cleveland, OH More articles by this author , and James FinkeJames Finke Cleveland, OH More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.370AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES We find that the tyrosine kinase receptor (TKR) inhibitor sunitinib, a front line treatment for metastatic renal cell carcinoma (RCC), reduces MDSC numbers in patient blood and tumor. Given the ability of MDSCs to synthesize both immunosuppressive- and TKR-independent angiogenic molecules, MDSC recruitment may be a means by which tumors become resistant to current anti-angiogenic treatments directed at tyrosine kinase signaling alone. Our goal is to elucidate the role of MDSC persistence in sunitinib resistant murine tumor models, and to assess whether specific tumor- or bone marrow (BM)-derived cytokines protect MDSCs from sunitinib therapy by modulating survival and/or immunosuppressive or angiogenic gene expression. METHODS Here we used the sunitinib sensitive RENCA (renal) and resistant 4T1 (mammary) murine tumor lines. Mice bearing 10mm tumors were treated or not with sunitinib (40mg/kg) for 6 days. Thereafter single cell suspensions of BM and tumor were stained with anti-Gr1 and anti-CD11b antibodies to assess the number and percentages of neutrophilic (n-MDSC, Gr1+hiCD11b+) and monocytic (m-MDSC, Gr1+lowCD11b+) MDSC subsets by FACS. RNA from FACS-sorted n-MDSCs and m-MDSCs from BM was subjected to real time PCR to assess the effect of sunitinib on gene expression. RESULTS n-MDSCs and m-MDSCs decreased 20 fold and 10 fold, respectively, in sunitinib-treated RENCA tumors as compared to untreated controls, whereas neither MDSC subpopulation was detectably diminished in sunitinib-treated 4T1 tumors, or in the BM of mice carrying either sunitinib-treated RENCA or 4T1 tumors. Interestingly, of the multiple angiogenic and immunosuppressive genes that were assessed in BM MDSCs, the only significant modulation observed was a 4 fold stimulation of BV8 expression by the m-MDSC subset in the sunitinib-treated 4T1-bearing animals. CONCLUSIONS The persistence of MDSCs within tumor and BM may represent a mechanism of cancer resistance to sunitinib. Further studies will elucidate the means by which MDSCs persist despite sunitinib treatment, and will determine if overcoming MDSC accumulation affects outcomes. It may be that increased expression of GM-CSF, G-CSF, or IL-1 beta within 4T1 tumors will correlate with MDSC survival and persistence. In addition it may be the case that sunitinib mediates its antitumor effects by inhibiting MDSC gene expression in susceptible tumors. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e126 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kevin Chandler Cleveland, OH More articles by this author Charles Tannenbaum Cleveland, OH More articles by this author James Finke Cleveland, OH More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...