MP35-17 COMBINATION OF MTOR INHIBITION AND CD4 DEPLETION GENERATES ANTITUMOR IMMUNITY

Abstract

You have accessJournal of UrologyKidney Cancer: Basic Research III1 Apr 2014MP35-17 COMBINATION OF MTOR INHIBITION AND CD4 DEPLETION GENERATES ANTITUMOR IMMUNITY Yanping Wang, Tim Sparwasser, Robert Figlin, and Hyung L. Kim Yanping WangYanping Wang More articles by this author , Tim SparwasserTim Sparwasser More articles by this author , Robert FiglinRobert Figlin More articles by this author , and Hyung L. KimHyung L. Kim More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.1060AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Effective immune stimulation produces long-lasting memory lymphocytes. The mTOR (mechanistic target of rapamycin) pathway is an important checkpoint that governs the formation of CD8 memory cells. However, mTOR inhibition also suppresses the immune system at least in part by enhancing CD4 regulatory T cell (Treg) activity. Therefore we explored a combination therapy targeting the mTOR pathway (temsirolimus) and Tregs. METHODS Tregs were controlled with CD4 depleting antibodies because CD4 depletion has high translational potential and already has a well-established safety profile in patients. In mouse models we verified that Treg depletion is the mechanism of immune stimulation mediated by CD4 depletion; Tregs were specifically depleted using DEREG (DEpletion of REGulatory T cells) transgenic mice, which carry a diphtheria toxin receptor transgene under the control of the Foxp3 promoter. Transgenic mice with green fluorescence protein (GFP)-marked Tregs were used to replace Tregs after CD4 depletion. Immune stimulation was monitored by assessing subcutaneous and metastatic tumor growth, and assessing CD8 T cell function (IFN-γ response and in vivo cytotoxic T lymphocytes assay). Immune memory was assessed using memory markers in CD8 T cells (e.g. Eomes, CD62L, BCL2) and assessing immune recall after secondary immune stimulation. RESULTS The antitumor activity of the combination therapy was CD8 dependent and controlled growth of syngeneic tumors even when an adoptive immunotherapy was not used. The timing of CD4 depletion was critical to allow for CD4 helper function during primary immune stimulation. Lymphocytes resulting from the combination therapy could be transferred into naïve mice to inhibit aggressive growth of lung metastases. The combination therapy enhanced CD8 memory formation as determined by memory markers and functional studies of immune recall. Removal of FoxP3 expressing T lymphocytes was the mechanism underlying immune stimulation and memory formation following CD4 depletion. This was confirmed using transgenic DEREG mice to specifically remove Tregs. It was further confirmed with reciprocal studies where immune stimulation due to CD4 depletion was completely neutralized by adoptively transferring tumor-specific Tregs. Also contributing to tumor control, Tregs that eventually recovered following CD4 depletion were less immunosuppressive. CONCLUSIONS These results provide a rationale for further study of mTOR inhibition and Treg depletion using anti-CD4 antibodies in cancer patients. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e377 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Yanping Wang More articles by this author Tim Sparwasser More articles by this author Robert Figlin More articles by this author Hyung L. Kim More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...