93 SUPPRESSION OF TUMOR-DERIVED TRANSFORMING GROWTH FACTOR-β(TGF-β) SIGNALING IN PROSTATE CANCER CELLS INCREASES TUMOR REACTIVE MEMORY CD8+ T CELLS

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research I1 Apr 201093 SUPPRESSION OF TUMOR-DERIVED TRANSFORMING GROWTH FACTOR-β(TGF-β) SIGNALING IN PROSTATE CANCER CELLS INCREASES TUMOR REACTIVE MEMORY CD8+ T CELLS Lin Chen, Thomas Jang, Norm Smith, Borko Javonovic, Lihua Zhu, Chung Lee, and Qiang Zhang Lin ChenLin Chen Chicago, IL More articles by this author , Thomas JangThomas Jang New Brunswick, NJ More articles by this author , Norm SmithNorm Smith Chicago, IL More articles by this author , Borko JavonovicBorko Javonovic Chicago, IL More articles by this author , Lihua ZhuLihua Zhu Boston, MA More articles by this author , Chung LeeChung Lee Chicago, IL More articles by this author , and Qiang ZhangQiang Zhang Chicago, IL More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.142AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES TGF-β is a potent immunosuppressant. In previous studies, we showed that overproduction of TGF-β by prostate cancer results in evasion of the host immune surveillance and tumor progression. Active memory CD8+ T cells were reported as the major tumoricidal cells, and their absence was associated with a worse prognosis. In the current study, we show that suppressing tumor-derived TGF-β increases tumor reactive memory CD8+ T cells, which may in turn inhibit tumor progression. METHODS ELISA assays were performed to determine TGF-β evels expressed by TRAMP-C2 cells, a mouse prostate cancer cell line. To induce tumor reactive memory CD8+ T cells in vivo, C57BL/6 mice were primed with irradiated TRAMP-C2 cells (5 x 106 per mice at 20,000 Ci) by s.c. injection every 7 days for a total of 7 inoculations. Splenic CD8+ T cells were isolated, then co-cultured with TRAMP-C2 cells in vitro and exposed for 72 hours according to the following groups: 1) no treatment (control); 2) external TGF-β (10ng/ml); 3) a neutralizing monoclonal antibody (clone 1D11) against TGF-β-1, -2, -3 at 100ug/ml; 4) an isotype control antibody, 13C4 at 100ug/ml. CD44+CD62L+CD8+TCR+ memory CD8+ T cells were identified by using immunofluorescent quadruple-stainning with the following antibodies conjugated with fluoresent: anti-CD44 (PE), -TCR β chain (APC), -CD8 (FITC) and -CD62L (PE CyTM7). Results were tested by flow cytometry. RESULTS High levels of TGF-β expression were identified in TRAMP-C2 cells at an amount of 175pg/105/48hours, which is much higher than any other prostate cancer cells that we reported previously. There were no significant differences between group 1 (6.2¡À0.6%), group 2 (7.1¡À0.7%) and group 4 (6.8¡À0.5%) above in terms of presence of CD44+CD62L+CD8+TCR+ memory CD8+ T cells, respectively. After treatment with 1D11, there was a significant increase in memory CD8+ T cells when compared to other groups (14.4¡À0.4%, p<0.01), suggesting that tumor-derived TGF-β as opposed to externally derived TGF-β inhibits the memory T cells. Finally, active memory CD8+ T cells could be recovered and generated when tumor-derived TGF-β was neutralized by 1D11. CONCLUSIONS The role of TGF-β on memory CD8+ T cells in prostate cancer is not well defined. Our study demonstrates that overexpression of TGF-β in prostate cancer can inhibit the generation of memory CD8+ T cells. Inhibiting TGF-β in vivo by neutralizing antibody is a potential novel immunotherapeutic approach to recover memory T cells, which may in turn inhibit tumor progression. © 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e38-e39 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Lin Chen Chicago, IL More articles by this author Thomas Jang New Brunswick, NJ More articles by this author Norm Smith Chicago, IL More articles by this author Borko Javonovic Chicago, IL More articles by this author Lihua Zhu Boston, MA More articles by this author Chung Lee Chicago, IL More articles by this author Qiang Zhang Chicago, IL More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...