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Enhancing Monocyte Effector Functions in Antibody Therapy Against Cancer

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Enhancing Monocyte Effector Functions in Antibody Therapy Against Cancer Enhancing monocyte effector functions in antibody therapy against cancer Dissertation Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Kavin Fatehchand, B.S. Biomedical Sciences Graduate Program The Ohio State University 2018 Dissertation Committee: Susheela Tridandapani, Ph.D., Advisor John C. Byrd, M.D. Larry Schlesinger, M.D. Tatiana Oberyszyn, Ph.D. Copyrighted by Kavin Fatehchand 2018 Abstract The immune system plays an important role in the clearance of pathogens and tumor cells. However, tumor cells can develop the ability to evade immune destruction, making the interaction between the immune system and the tumor an important area of research. The overall goal in my graduate studies, therefore, was to find different ways to enhance the innate immune response against cancer cells. First, I focused on monoclonal antibody therapy with reference to the role of monocytes/macrophages as immune effectors. Tumor-specific antibodies bind to cancer cells and create immune-complexes that are recognized by IgG receptors (FcγR) on these immune effector cells. FcγRIIb is the sole inhibitory FcγR that negatively regulates monocyte/macrophage effector responses. In the first part of this study, I examined the ability of the TLR4 agonist, LPS, to enhance macrophage FcγR function. I found that TLR4 activation led to the down-regulation of FcγRIIb through the activation of the March3 ubiquitin ligase. Although monocytes play an important role in tumor clearance, tumor cells can develop immune evasion. Acute Myeloid Leukemia (AML) is a hematologic malignancy caused by the proliferation of immature myeloid cells, which accumulate in the bone marrow, peripheral blood, and other tissues. The progression of AML is partially dependent on immune cell evasion by AML blasts. Since AML cells are of myeloid origin, I next focused on shifting this blast phenotype from an immunosuppressive to i effector-like phenotype. IFNγ is known to polarize macrophages to an anti-tumor M1-like state. Since AML cells are of myeloid origin, we hypothesized that IFNγ would be able to shift the phenotype of AML cells to more of an effector state. In these studies, I found that AML blasts can indeed be shifted into a more anti-tumor/M1 by IFNγ. Importantly, IFNγ was also able to up-regulate FcγRI and the antibody target CD38. When AML blasts were treated with the combination of IFNγ and the anti-CD38 antibody, daratumumab, there were significant increases in cytotoxicity, suggesting that these cells were killing each other, which we term daratumumab-mediated fratricide. Extending these observations, I examined whether Type 1 IFNs, much like IFN!, could initiate daratumumab-mediated fratricide in AML. Type 1 IFNs have been used in AML clinical trials before, however, they lose their effect in patients due to their short serum half-life. In order to overcome this problem, I explored the possibility of increasing endogenous Type 1 IFNs by targeting plasmacytoid Dendritic Cells (pDCs) through TLR 7/8 stimulation. Consistent with this notion, R848-treated pDCs had increased markers of pDC activation and an enhanced Type 1 IFN response. IFNβ was also able to shift AML cells to an M1-like phenotype, increase the antibody target CD38, and enhance daratumumab-mediated toxicity. These findings suggest that it is possible to overturn the tolerogenic phenotype of pDCs in AML, and also demonstrate a possible means of enhancing endogenous Type 1 IFN production for the purpose of inducing daratumumab-mediated fratricide of AML blasts. In the final part of this dissertation, I explored the utility of natural products in AML therapy. To this end, I examined the effect of the natural product, Active Hexose ii Correlated Compound (AHCC) on AML. I found that AHCC induced extrinsically- mediated apoptosis in AML cells. When tested in a murine engraftment model of AML, AHCC led to significantly increased survival time and decreased blast counts. These results lend support for the further investigation of AHCC as a potential adjuvant for the treatment of AML. Taken together, these studies have uncovered multiple ways to target the innate immune system, the immunosuppressive tumor cell, or both in order to fight cancer. In Chapter 2, I focused on enhancing monocyte FcγR-mediated effects against cancer. In Chapters 3 and 4, I demonstrated a novel way to shift cancer cells themselves to a more effector-like state in the context of antibody therapy against AML. Finally, in Chapter 5, I used a natural product that was able to target both monocytes and AML cells in opposite ways. iii Dedication This dissertation is dedicated to my family and friends. iv Acknowledgments First and foremost, I would like to thank the most supporting, kind, and brilliant advisor, Dr. Susheela Tridandapani for her continual guidance and support throughout my pre-doctoral training. Dr. Tridandapani has been there for every step of my graduate career and I cannot thank her enough for her leadership and direction. Additionally, I would like to thank the members of my committee including Dr. John C. Byrd, Dr. Larry Schlesinger and Dr. Tatiana Oberyszyn who have helped me throughout my training. Dr. Byrd, I want to thank you for teaching me so much about AML and the research process. Dr. Schlesinger, I cannot thank you enough for being such an advocate for my career and Dr. Oberyszyn, I appreciate all your help on such short notice. I cannot wait to continue to work with all three of you during the rest of my career. I would also like to thank all past and present members of the Tridandapani laboratory. My journey in the lab started as an undergraduate at Emory University in 2009. Firstly, I would like to thank both Payal Mehta and Prexy Shah for training me during my initial few months in the lab. You inspired me to seek a career in science, and for that I am forever grateful. I would also like to thank past members, Devyn Gillette, Saranya Elavazhagan, Li Ren, and Shalini Gautam for their moral support during my graduate career. You have all become friends throughout my time here and my time with you all has been invaluable. For my fellow graduate students, Nate Buteyn and Giovanna v Merchand-Reyes, thank you for being there during times of stress and times of success these past few years. Additionally, I would like to give thanks to all the undergraduate students that I have been able to mentor including Brenda Shen, Hafza Inshaar, Ericka Erickson, and Reema Navalurkar. Finally, I have to thank Jon Butchar who has been in the lab with me since the beginning, guiding me. He has been instrumental in my success as a graduate student and I am forever thankful. I must also acknowledge the faculty and staff at both the Biomedical Sciences Graduate Program and Medical Scientist Training program. Specifically, I would like to thank Dr. Larry Schlesinger, Dr. Larry Kirschner, and Ashley Bertran for their guidance in the MSTP program. Most importantly, I have to thank Amma, Thathi, Akku, the rest of my family, friends, partner Joey and his family, and Gerber & Daisy for their continued support. The strong women in my life including my Amma, Akku, Aththa, Chootzi, Loku Amma, Shani Nanda, Lakna and all my other cousins have truly taught me how to be independent, caring, and passionate in everything I do. Thank you so much for rooting for me throughout my life and making me realize the importance of the little things. I love you all so much. vi Vita May 24, 1992………………..Born – Chennai, India 2009-2013……………….......B.S. Biology, Emory University 2013-present………………...Medical Scientist Training Program, The Ohio State University Publications Cremer, T. J., Fatehchand, K., Shah, P., Gillette, D., Patel, H., Marsh, R. L., Besecker, B. Y., Rajaram, M. V., Cormet-Boyaka, E., Kanneganti, T. D., Schlesinger, L. S., Butchar, J. P., and Tridandapani, S. (2012) MiR-155 induction by microbes/microbial ligands requires NF-kappaB-dependent de novo protein synthesis. Front Cell Infect Microbiol 2, 73 Shah, P., Fatehchand, K., Patel, H., Fang, H., Justiniano, S. E., Mo, X., Jarjoura, D., Tridandapani, S., and Butchar, J. P. (2013) Toll-like receptor 2 ligands regulate monocyte Fcgamma receptor expression and function. J Biol Chem 288, 12345-12352 Justiniano, S. E., Elavazhagan, S., Fatehchand, K., Shah, P., Mehta, P., Roda, J. M., Mo, X., Cheney, C., Hertlein, E., Eubank, T. D., Marsh, C., Muthusamy, N., Butchar, J. P., Byrd, J. C., and Tridandapani, S. (2013) Fcgamma receptor-induced soluble vascular endothelial growth factor receptor-1 (VEGFR-1) production inhibits angiogenesis and enhances efficacy of anti-tumor antibodies. J Biol Chem 288, 26800-26809 Gillette, D. D., Curry, H. M., Cremer, T., Ravneberg, D., Fatehchand, K., Shah, P. A., Wewers, M. D., Schlesinger, L. S., Butchar, J. P., Tridandapani, S., and Gavrilin, M. A. (2014) Virulent Type A Francisella tularensis actively suppresses cytokine responses in human monocytes. Front Cell Infect Microbiol 4, 45 Elavazhagan, S., Fatehchand, K., Santhanam, V., Fang, H., Ren, L., Gautam, S., Reader, B., Mo, X., Cheney, C., Briercheck, E., Vasilakos, J. P., Dietsch, G. N., Hershberg, R. M., Caligiuri, M., Byrd, J. C., Butchar, J. P., and Tridandapani, S. (2015) Granzyme B expression is enhanced in human monocytes by TLR8 agonists and contributes to antibody-dependent cellular cytotoxicity. J Immunol 194, 2786-2795 vii Ren, L., Campbell, A., Fang, H., Gautam, S., Elavazhagan, S., Fatehchand, K., Mehta, P., Stiff, A., Reader, B. F., Mo, X., Byrd, J. C., Carson, W. E., 3rd, Butchar, J. P., and Tridandapani, S. (2015) Analysis of the effects of the Btk inhibitor ibrutinib on monocyte FcgammaR function. J Biol Chem Fatehchand, K., Ren, L., Elavazhagan, S., Fang, H., Mo, X., Vasilakos, J.
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