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(BTLA) in CD8 TUMOR INFILTRATING LYMPHOCYTES Krit Ritthipichai

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(BTLA) in CD8 TUMOR INFILTRATING LYMPHOCYTES Krit Ritthipichai The Texas Medical Center Library DigitalCommons@TMC The University of Texas MD Anderson Cancer Center UTHealth Graduate School of The University of Texas MD Anderson Cancer Biomedical Sciences Dissertations and Theses Center UTHealth Graduate School of (Open Access) Biomedical Sciences 8-2016 MECHANISTIC AND FUNCTIONAL CHARACTERIZATION OF B AND T LYMPHOCYTE ATTENUATOR (BTLA) IN CD8 TUMOR INFILTRATING LYMPHOCYTES krit ritthipichai Follow this and additional works at: https://digitalcommons.library.tmc.edu/utgsbs_dissertations Part of the Medicine and Health Sciences Commons Recommended Citation ritthipichai, krit, "MECHANISTIC AND FUNCTIONAL CHARACTERIZATION OF B AND T LYMPHOCYTE ATTENUATOR (BTLA) IN CD8 TUMOR INFILTRATING LYMPHOCYTES" (2016). The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access). 685. https://digitalcommons.library.tmc.edu/utgsbs_dissertations/685 This Dissertation (PhD) is brought to you for free and open access by the The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences at DigitalCommons@TMC. It has been accepted for inclusion in The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access) by an authorized administrator of DigitalCommons@TMC. For more information, please contact [email protected]. MECHANISTIC AND FUNCTIONAL CHARACTERIZATION OF B AND T LYMPHOCYTE ATTENUATOR (BTLA) IN CD8 TUMOR INFILTRATING LYMPHOCYTES by Krit Ritthipichai, D.V.M., M.S. APPROVED: _____________________________ Patrick Hwu, M.D. Supervisory Professor ______________________________ Chantale Bernatchez, Ph.D ______________________________ Greg Lizee, Ph.D ______________________________ Roza Nurieva, Ph.D ______________________________ Thomas Cooper, M.D. APPROVED: ______________________________ Dean, The University of Texas Graduate School of Biomedical Sciences at Houston i MECHANISTIC AND FUNCTIONAL CHARACTERIZATION OF B AND T LYMPHOCYTE ATTENUATOR (BTLA) IN CD8 TUMOR INFILTRATING LYMPHOCYTES A DISSERTATION Presented to the Faculty of The University of Texas Health Science Center at Houston and The University of Texas M. D. Anderson Cancer Center Graduate School of Biomedical Sciences in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY By Krit Ritthipichai, D.V.M., M.S. Houston, Texas August, 2016 ii DEDICATION To my father, thank you for inspiring me to work on cancer immunology. To my mother, thank you for your sacrifice, support, and encouragement. To my brothers, thank you for your patience and encouragement. iii ACKNOWLEDGEMENTS I would like to thank my advisors, Drs. Patrick Hwu, Chantale Bernatchez, and Laszlo Radvanyi for their guidance. Dr. Hwu, thank you for your patience and support, you always challenge me to do the best. Thank you Chantale for always being there for me. Your support and encouragement have helped me surpass obstacles. Thank you Laszlo for giving me an opportunity to be in the field of adoptive T cell therapy. I would also like to thank my committee members: Thank you Drs. Roza Nurieva Greg Lizee and Thomas Cooper for your great support and encouragement. Thank you to previous and current members of the Bernatchez and Radvanyi lab: Cara Haymaker, Marie Andree Forget, Geok Choo Sim, Jessica Chacon, Michiko Harao, Richard Wu, Charuta Kale, Caitlin Creasy, Kelly Bowen, Young Uk Kim, Donald Sakellariou-Thompson, and Lorenzo Federico. Thank you for all your wonderful support and unforgettable memories. Thank you to my fellowship advisors (Drs. Ness, Mullen, and Loose) and past and current CPRIT fellows. iv MECHANISTIC AND FUNCTIONAL CHARACTERIZATION OF B AND T LYMPHOCYTE ATTENUATOR (BTLA) IN CD8 TUMOR INFILTRATING LYMPHOCYTES Krit Ritthipichai, D.V.M., M.S. Supervisory Professor: Patrick Hwu, MD This dissertation project focused on understanding the functional role of BTLA on CD8+ Tumor Infiltrating Lymphocytes (TIL) from metastatic melanoma patients. Clinical trials of adoptive T-cell therapy (ACT) using autologous ex vivo expanded TIL have demonstrated the great potential of this immunotherapy with an overall clinical response rate 40-50% for stage IV metastatic melanoma patients. We have investigated a number of biomarkers in both the infused TIL and the tumor microenvironment for their association with clinical response. Surprisingly, a subset of CD8+ TIL expressing the co-inhibitory molecule BTLA (B-and-T lymphocyte attenuator) was highly associated with clinical response, while expression of other co-inhibitory molecules such as PD-1, TIM-3, and Lag3 did not associate with response. BTLA is expressed by T cells, B cells, and NK cells and serves as a T cell differentiation maker whereby high expression of BTLA associates with less differentiated T cell phenotype. While the suppressive function of the ITIM and ITSM motifs of BTLA are well described, the Grb2 motif’s function remains understudied. In this study, we sought to determine the functional characteristics of the CD8+BTLA+TIL subset and define the contribution of the Grb2 motif of BTLA in T cell co-stimulation. We have uncovered a survival advantages of the BTLA+ subset that allows for serial killing of target tumor cells, which may explain our previous v correlation between this subset and response to TIL ACT. BTLA-HVEM interaction during T cell activation led to the specific activation of SRC kinase. In addition, our results unveiled a role for the BTLA-associated Grb2-binding motif in T cell proliferation and IL-2 production following TCR engagement that was independent of the inhibitory function of ITIM/ITSM motifs. Overall, our study first unveil the dual role of BTLA as both a co-stimulatory and co-inhibitory molecule. The integration of the positive and negative signals transduced by BTLA promotes IL-2 secretion while reducing certain effector function of T cell. Altogether, the combination of both BTLA signaling and inherent attributes of less differentiated T cells could promote T cell survival, persistence, and anti-tumor function. vi TABLE OF CONTENTS Approval Signatures………………………………………………………… i Title Page…………………………………………………………………….. ii Dedication……………………………………………………………………. iii Acknowledgements…………………………………………………………... iv Abstract………………………………………………………………………. v Table of Contents……………………………………………………………. viii List of Figures………………………………………………………………... x List of Tables………………………………………………………………… xiii Abbreviations………………………………………………………………… xiv CHAPTER 1: General Introduction……………………………………….. 1.1 Cancer Immunotherapy 1.1 a) Highlights of major discoveries in cancer immunotherapy……… 2 1.1 b) Checkpoint inhibitors………………………………………………. 8 1.1 c) Cancer vaccine……………………………………………………... 12 1.1 d) Cytokine therapy for cancers ……………………………………… 17 1.2 Cell based therapy for malignant diseases 1.2 a) NK cell therapy…………………………………………………….. 21 1.2 b) T cell therapy (Adoptive T cell therapy (ACT), Chimeric Antigen Receptor T cell therapy (CAR), and Endogenous T cell therapy…. 24 1.3 Biomarker of immune cells: Immunoscore…………………………….. 38 1.4 Co-signaling molecule on T cells 1.4 a) Co-stimulatory molecules………………………………………… 40 vii 1.4 b) Co-inhibitory molecules ………………………………………….. 46 1.5 B and T lymphocytes attenuator (BTLA) 1.5 a) Discovery of BTLA and its ligand…………………………………. 49 1.5 b) BTLA structure and functions…………………………………….. 51 1.5 c) BTLA in murine disease models…………………………………… 53 1.6 Main theoretical question posed in this dissertation ………………..... 58 1.7 Overall hypothesis and Specific Aims………………………………...... 60 CHAPTER 2: Transcriptional analysis of BTLA in metastatic melanoma patients and comparative study of BTLA kinetic expression in CD8+lymphocyte…………………………………………………………….. 2.1 Rationale and Hypothesis……………………………………………. 62 2.2 Results………………………………………………………………… 64 2.3 Discussion…………………………………………………………….. 80 CHAPTER 3: Characterization of anti-tumor capacity of CD8+BTLA+TIL subset……………………………………………………… 3.1 Rationale and Hypothesis……………………………………………. 83 3.2 Results………………………………………………………………… 85 3.3 Discussion…………………………………………………………….. 103 CHAPTER 4: Functional study of B and T lymphocyte in murine model... 4.1 Rationale and Hypothesis…………………………………………... 106 4.2 Results………………………………………………………………… 108 4.3 Discussion…………………………………………………………….. 123 viii CHAPTER 5: Dissecting BTLA signaling pathway in murine T lymphocytes and human tumor infiltrating lymphocytes (TIL)…………... 5.1 Rationale and Hypothesis……………………………………………. 126 5.2 Results………………………………………………………………… 128 5.3 Discussion…………………………………………………………….. 144 CHAPTER 6: Investigation of BTLA function in in vivo tumor control….. 6.1 Rationale and Hypothesis……………………………………………. 147 6.2 Results…………………………………………………........................ 148 6.3 Discussion……………………………………………………………... 157 CHAPTER 7: Functional role of BTLA in T cell priming and memory recall response………………………………………………………………... 7.1 Rationale and Hypothesis…………………………………………… 160 7.2 Results………………………………………………………………… 161 7.3 Discussion…………………………………………………………….. 165 CHAPTER 8: OVERALL DISCUSSION AND FUTURE DIRECTION… 166 CHAPTER 9: MATERIALS and METHODS…………………........... 178 CHAPTER 10: REFERENCES……………………………………… 191 CHAPTER 11: VITA……………………………………………….. 226 ix LIST OF FIGURES CHAPTER 1. 1.1 Schematic diagram demonstrates four major types of cancer 7 immunotherapy…………………………………………………………. 1.2 Schematic diagram of the process of TIL expansion and TIL therapy…. 26 CHAPTER 2. 2.1 Association of high CD8a and high BTLA transcription
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