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Interferon-Alpha Immunotherapy of Melanoma: Signal Transduction, Gene Transcription, and the Role of Suppressor of Cytokine Signaling Proteins in Immune Cells

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Interferon-Alpha Immunotherapy of Melanoma: Signal Transduction, Gene Transcription, and the Role of Suppressor of Cytokine Signaling Proteins in Immune Cells INTERFERON-ALPHA IMMUNOTHERAPY OF MELANOMA: SIGNAL TRANSDUCTION, GENE TRANSCRIPTION, AND THE ROLE OF SUPPRESSOR OF CYTOKINE SIGNALING PROTEINS IN IMMUNE CELLS DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Jason M. Zimmerer, B.S. ***** The Ohio State University 2007 Dissertation Committee: Approved by William E. Carson, III, M.D., Advisor Virginia Sanders, Ph.D. _________________________________ Anne VanBuskirk, Ph.D. Advisor Integrated Biomedical Sciences Mathew Ringel, M.D. Graduate Program i ABSTRACT High dose interferon-alpha-2b (IFN-α-2b) is employed as an adjuvant therapy in melanoma patients who have undergone surgical resection of high-risk lesions. The precise molecular targets of IFN-α therapy are unknown, but likely involve signal transducer and activator of transcription 1 (STAT1) signal transduction within host immune effector cells. We hypothesized that STAT1-mediated signaling induces molecular targets important for mediating the anti-tumor effect of exogenously administered IFN-α. To identify the STAT1-dependent genes, microarray technology was utilized to characterize the gene expression profile of splenocytes from wild type (WT) and STAT1-/- mice stimulated with IFN-α. Analysis showed that 25 genes required STAT1 signal transduction for optimal expression in response to IFN-α (i.e. Gzmb, Isg20, Ly6c; p < 0.001). Interestingly, human immune cells are also capable of inducing the homologues of these genes in response to IFN-α. Human PBMCs, CD3+ T cells, CD56+ natural killer (NK) cells, and CD14+ monocytes each exhibited a distinct and reproducible transcriptional profile following stimulation with IFN-α by microarray analysis. Analysis of gene expression within PBMCs from melanoma patients (n = 7) receiving high-dose IFN-α-2b (20 MU/m2 i.v.) also revealed significant upregulation of 23 genes (including IRF7, TAP1, TNFRSF6, USP18; p < 0.001). A comparison of the gene expression profile of in vitro IFN-α-stimulated PBMCs from normal donor cells ii with that of PBMCs obtained from melanoma patients receiving intravenous IFN-α revealed little overlap. However, within individual patients, the gene expression profile of in vitro IFN-α-stimulated PBMCs was largely predictive of the expression profile of gene expression following IFN-α administration. This indicated that an individual patient response to IFN-α immunotherapy could be predicted prior to treatment. The phosphorylation of STAT1 (P-STAT1) within effector cells is highly variable among melanoma patients following IFN-α immunotherapy and at high doses of IFN-α P-STAT1 is down-regulated. We hypothesized that high doses of IFN-α administration would yield suboptimal levels of signal transduction and gene transcription and the induction of inhibitors by IFN-α may be the cause. PBMCs collected from metastatic melanoma receiving escalating doses of IFN-α-2b (5 MU/m2 and then 10 MU/m2) exhibited statistically equivalent levels of P-STAT1, P-STAT2 and the induction of interferon stimulated gene (ISG) transcripts. In addition, suppressors of cytokine signaling (SOCS) protein 1 and SOCS3 were induced to a greater degree with the higher dose of IFN-α. This suggests that a negative feedback loop is activated, thus inhibiting the effect of the higher dose. In fact, SOCS1 and SOCS3 are involved in the negative regulation of IFN-α activity including STAT1 activation and ISG transcription in vitro. The loss of function of SOCS1 and SOCS3 reveals that the anti-tumor effects of IFN-α can be enhanced in the mouse model of malignant melanoma. Impressively, IFN-α treatment eliminated lethal inoculums of melanoma in 70% of SOCS1-deficient mice, whereas all IFN-treated SOCS1-competent mice died. The anti-tumor effects of IFN-α in iii tumor-bearing SOCS1-deficient mice were markedly inhibited following depletion of CD8+ T cells. These results indicate that the anti-tumor response of immune effector cells to exogenous IFN-α is regulated by SOCS proteins. Additionally, we show that SOCS1 was an important regulator of immunosurveillance of developing cancer as SOCS1-deficient mice were protected from tumor formation. These reports are the first to characterize the dependence of STAT1 in mediating the transcriptional response of immune cells to IFN-α. In addition, the studies remain the first to define the transcriptional response of immune subsets to IFN-α and to characterize the transcriptional profiles of PBMCs from melanoma patients undergoing IFN-α immunotherapy. We also determined that microarray analysis of patient PBMCs following in vitro stimulation with IFN-α may be a useful predictor of the individual response to IFN-α immunotherapy. Finally, the optimization of the dose of IFN-α administration and the modulation of SOCS activity may allow for a greater efficacy of IFN-α immunotherapy. iv Dedicated to the women of my life, both past and present: Jennifer, Christine, and Patricia. You are my life, my guide, and my motivation. v ACKNOWLEDGMENTS This work would not have been possible were it not for the support of numerous individuals. First, I would like to thank my mentor William Carson. Dr. Carson has been a tremendous motivator these last four years and I feel privileged to have worked in his laboratory. He has been not only a caring physician and a diligent investigator, but a dedicated teacher to young researchers. I would also like to thank the members of Carson lab and collaborators for their support and friendship. Specifically, I would like to recognize Dr. Gregory Lesinski, Sri Vidya Kondadasula, Volodymyr Karpa, Dr. Brian Becknell, Amy Lehman, Amy Ruppert, Dr. Michael Radmacher, Dr. James Ihle, Dr. Sushella Tridandapani, Dr. Michael Caligiuri, Dr. Thomas Olencki, Dr. Kari Kendra, Dr. Michael Walker, and the CCC Core laboratories. Additionally, I would like to offer my genuine appreciation to the members of my graduate dissertation committee, namely Virginia Sanders, Anne Vanbuskirk, and Mathew Ringel for their time and advice. Finally, I would like to recognize my family for their love and encouragement. I would like to thank my parents, Chris and Michael, for their dedication to my upbringing and their continuous stress of academics. I only hope that I will raise my children with the same values. Most of all I want to recognize my wife, Jennifer. She has supported me with love, understanding, and patience during the long hours spent apart due to my time in the laboratory. She is my center, my heart, my home. vi VITA November 2, 1979. Born – Dayton, Ohio. 2002. Bachelors of Science- Biochemistry Ohio Northern University, Ada, OH. 2002 – present. Ph.D. Candidate, Integrated Biomedical Sciences Graduate Program, The Ohio State University PUBLICATIONS Research Publications 1. Lesinski, G.B., M. Anghelina, J. Zimmerer, T. Bakalakos, B. Badgwell, R. Parihar, Y. Hu, G. Abood, C. Magro, J. Durbin and W.E. Carson. The anti-tumor effects of interferon-alpha are abrogated in a STAT1-deficient mouse. Journal of Clinical Investigation 112(2): 170-180, 2003. 2. Lesinski, G.B., B. Badgwell, J. Zimmerer, T. Crespin, Y. Hu, G. Abood and W.E. Carson. Interleukin-12 pre-treatments enhance interferon-alpha-induced Jak-STAT signaling and potentiate the anti-tumor effects of interferon-alpha in a murine model of malignant melanoma. Journal of Immunology 172(12):7368-76, 2004. FIELDS OF STUDY Major Field: Integrated Biomedical Sciences Graduate Program vii TABLE OF CONTENTS P a g e Abstract. ii Dedication. v Acknowledgments . .vi Vita . vii List of Tables. x List of Figures . .xi List of Abbreviations . .xiii Chapters: 1. Introduction...…………………………………………...…………………............1 1.1 Interferon-alpha……….....……………………………………...1 1.2 Melanoma…….....……….……………………..……….............3 1.3 Treatment of melanoma................................................................5 1.4 Potential anti-tumor mechanisms of IFN-α…….……….....…....8 1.5 Suppressors of cytokine signaling proteins…….………………10 1.6 Hypothesis………..……………...….………….………………11 2. The role of STAT1 in mediating the transcription of interferon stimulated genes in murine immune cells……………………………………………………………..............13 2.1 Introduction……………………………..……………………..13 2.2 Materials and Methods………………………………………...15 2.3 Results……………………………………..…………………..18 2.4 Discussion………………………………..……………………19 2.5 Tables and Figures…...…………………..……………………22 3. Gene expression profiling of the immune response to interferon-alpha…............28 viii 3.1 Introduction……………………….……………………...…...28 3.2 Materials and Methods……………………...………………...30 3.3 Results.………………………………………………………..34 3.4 Discussion.……………………………………………………39 3.5 Tables and Figures…..…………………..……………………44 4. Interferon-alpha-2b induced signal transduction and gene regulation in patient PBMCs is not enhanced by a dose increase from 5 MU/m2 10 MU/m2……………..…..58 4.1 Introduction………………………………………………......58 4.2 Materials and Methods……….….…………………………...60 4.3 Results………………………………………………………..63 4.4 Discussion……………………………………………………67 4.5 Tables and Figures….…………………..……………………71 5. IFN-alpha-induced signal transduction, gene expression, and anti-tumor activity of immune effector cells are negatively regulated by suppressor of cytokine signaling proteins…………………………………………………………………………………...86 5.1 Introduction………………………..…….………………......86 5.2 Materials and Methods………………………….…………...89 5.3 Results……………………….…….……………….………..95 5.4 Discussion………………….…….……………..….………104 5.5 Tables and Figures……………………….………..….……109 6. Conclusion……………………………………..…………...…………………...142
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