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UC San Diego UC San Diego Electronic Theses and Dissertations UC San Diego UC San Diego Electronic Theses and Dissertations Title Defining the Role of Nr4a Transcription Factors in CD8+ T Cell Exhaustion Using a Murine CAR T Cell Tumor Model Permalink https://escholarship.org/uc/item/5mj1t7tp Author Chen, Joyce Publication Date 2019 Supplemental Material https://escholarship.org/uc/item/5mj1t7tp#supplemental Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California UNIVERSITY OF CALIFORNIA SAN DIEGO Defining the Role of Nr4a Transcription Factors in CD8+ T Cell Exhaustion Using a Murine CAR T Cell Tumor Model A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Biomedical Sciences by Joyce Chen Committee in charge: Professor Anjana Rao, Chair Professor Victor Nizet, Co-Chair Professor Rafael Bejar Professor Christopher K. Glass Professor Ananda W. Goldrath 2019 © Joyce Chen, 2019 All rights reserved. ii The Dissertation of Joyce Chen is approved, and is acceptable in quality and form for publication on microfilm and electronically: Co-Chair Chair University of California San Diego 2019 iii EPIGRAPH The most difficult thing is the decision to act. The rest is merely tenacity. The fears are paper tigers. You can do anything you decide to do. You can act to change and control your life and the procedure. The process is its own reward. Amelia Earhart iv TABLE OF CONTENTS Signature Page .......................................................................................................................... iii Epigraph .................................................................................................................................... iv Table of Contents ....................................................................................................................... v List of Abbreviations ..................................................................................................................vii List of Supplemental Files ......................................................................................................... viii List of Figures ............................................................................................................................ ix Acknowledgements .................................................................................................................... xi Vita ...........................................................................................................................................xiv Abstract of the Dissertation ....................................................................................................... xv Chapter 1: Introduction ............................................................................................................... 1 1.1 Cancer Immunotherapy: Checkpoint Blockade Therapies............................................... 2 1.2 Cancer Immunotherapy: Chimeric Antigen Receptor T Cell Therapies ........................... 3 1.3 T Cell Exhaustion ........................................................................................................... 7 1.4 Scope of this Work........................................................................................................ 12 1.5 Conclusion and Future Directions ................................................................................. 13 1.6 Figures ......................................................................................................................... 14 1.7 References ................................................................................................................... 17 Chapter 2: CD8+ CAR Tumor-Infiltrating T Cells Exhibit Similarity to CD8+ Endogenous Tumor- Infiltrating T Cells ..................................................................................................... 22 Abstract ................................................................................................................................ 23 2.1 Introduction ................................................................................................................... 24 2.2 Results and Discussion ................................................................................................ 26 2.3 Conclusion .................................................................................................................... 31 2.4 Figures ......................................................................................................................... 32 2.5 Experimental Section .................................................................................................... 45 2.6 Acknowledgements....................................................................................................... 56 2.7 References ................................................................................................................... 57 Chapter 3: Nr4a Transcription Factors Limit CAR T Cell Function in Solid Tumors ................... 63 v Abstract ................................................................................................................................ 64 3.1 Introduction ................................................................................................................... 65 3.2 Results and Discussion ................................................................................................ 67 3.3 Conclusion .................................................................................................................... 73 3.4 Figures ......................................................................................................................... 75 3.5 Experimental Section .................................................................................................... 93 3.6 Acknowledgements..................................................................................................... 106 3.7 References ................................................................................................................. 107 vi LIST OF ABBREVIATIONS ATAC-seq assay for transposase-accessible chromatin using sequencing CAR chimeric antigen receptor hCD19 human CD19 antigen HCV hepatitis C virus HIV human immunodeficiency virus IFNg interferon gamma IL-2 interleukin 2 LCMV lymphocytic choriomeningitis virus NFAT nuclear factor of activated T cells Nr4a nuclear receptor subfamily 4 group A PD-1 programmed cell death 1 RNA-seq RNA-sequencing TCR t cell receptor TIM3 T cell immunoglobulin and mucin-containing domain-3 TILs tumor-infiltrating lymphocytes TNF tumor necrosis factor SIV simian immunodeficiency virus vii LIST OF SUPPLEMENTAL FILES Supplementary Table 1 Comparisons of gene expression program in CAR vs endogenous CD8+ T cells infiltrating B16-OVA-hCD19 tumor Supplementary Table 2 Comparisons of human CD8+ TILs infiltrating a human melanoma Supplementary Table 3 Comparisons of cells ectopically expressing Nr4a in CD8+ T cells in vitro. a) RNA-seq DESeq2 results comparing empty vector pMIN vs Nr4a1; b) RNA-seq DESeq2 results comparing empty vector pMIN vs Nr4a2; c) RNA-seq DESeq2 results comparing empty vector pMIN vs Nr4a3. Supplementary Table 4 Comparison of gene expression program in Nr4a TKO vs wild-type CD8+ CAR T cells infiltrating B16-OVA-hCD19 tumor Supplementary Table 5 Comparison of gene expression program in antigen-specific cells from LCMV-infected mice treated with anti-PDL1 or IgG control viii LIST OF FIGURES Chapter 1 Figure 1.1. Schematic of checkpoint blockade .............................................................. 14 Figure 1.2. Schematic of chimeric antigen receptor design ........................................... 15 Figure 1.3. Schematic of T cell response ...................................................................... 16 Chapter 2 Figure 2.1. Functional assessment of a human CD19-reactive chimeric antigen Receptor (CAR) ........................................................................................ 32 Figure 2.2. CAR, OT-I and endogenous CD8+ TILs isolated from B16-OVA-hCD19 tumors exhibit similar phenotypes ............................................................. 34 Figure 2.3. Tumor-bearing mice adoptively transferred with CAR and OT-I T cells exhibit similar tumor growth rates ............................................................ 35 Figure 2.4. CAR and endogenous CD8+ TILs exhibit similar gene expression and chromatin accessibility profiles ................................................................... 36 Figure 2.5. Adoptively transferred CD8+ CAR T cells infiltrating B16-OVA-hCD19 tumors exhibit gene expression profiles similar to those of endogenous CD8+ TILs (extended data for Figure 2.4) ............................................................ 37 Figure 2.6. Adoptively transferred CAR-expressing mouse CD8+ T cells infiltrating B16-OVA-hCD19 tumors exhibit chromatin accessibility profiles similar to those of endogenous CD8+ TILs (extended data for Figure 2.4) ................. 38 Figure 2.7. CAR and endogenous CD8+ PD-1highTIM3high TILs exhibit upregulation of Nr4a family members ................................................................................ 40 Figure 2.8. Mouse CD8+ TILs exhibit increased expression of Nr4a1, Nr4a2, Nr4a3 (extended data for Figure 2.7) .................................................................... 41 Figure 2.9. Human CD8+ TILs exhibit increased Nr4a family members in PD-1hi TIM3hi
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  • Revised January 2003
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