Defects in T Cell Trafficking and Resistance to Cancer Immunotherapy (Resistance to Targeted Anti-Cancer Therapeutics Book 9)

This volume focuses on recent advances in understanding T cells as key players in antitumor immune responses, and as a result T cell-based immunotherapy is starting to transform the treatment of advanced cancers. However, despite recent successes, many patients with cancer fail to respond to these treatments. Defective migration of T cells into and within tumors is considered as an important resistance mechanism to cancer immunotherapy. The volume includes three sections. The first section covers general knowledge about T cell trafficking during a normal immune response but also during tumor development. The second section provides an in-depth description of the different obstacles that prevent T cells from migrating and contacting tumor cells. The third section explores therapeutic strategies to improve trafficking of T cells into tumors and, thus, to enhance the effectiveness of cancer immunotherapy. Preface 6 Contents 8 Chapter 1: Basic Rules of T Cell Migration 10 1.1 Introduction 11 1.2 T Cell Recirculation Through Secondary Lymphoid Organs 13 1.3 Molecular Basis of Protrusion: Contraction Cycles that Confer T Cell Motility 15 1.4 Regulation of Small GTPase Activity 18 1.5 Balance Between Motility and Arrest Governs T Cell Activation 18 1.6 Imprinting of T Cell Dissemination After Activation 19 1.7 T Cell Motility in Non-lymphoid Organs 20 1.8 Challenges for T Cells Infiltrating into Tumor Sites 21 References 23 Chapter 2: Regulation of Anti-tumor T Cell Migration and Function: Contribution of Real-Time Imaging 29 2.1 Introduction 31 2.2 Basic Principles of Intravital Imaging 32 2.3 Induction of Anti-tumor T Cell Activation and Recruitment 35 2.3.1 Tumor Antigen Recognition by T Cells 35 2.3.2 Regulation of Anti-tumor T Cell Priming 36 2.4 Regulation of the Intra-tumoral Localization and Trafficking of T Cells 39 2.4.1 Antigen Specificity, T Cell Recruitment and Retention Within Tumors 40 2.4.2 Control of T Cell Infiltration by Vessels Architecture 42 2.4.3 Control of Intratumoral T Cell Migration by the ECM 43 2.5 Imaging Antitumor T Cell Effector Functions and Immunosuppression 44 2.5.1 Imaging T Cell Cancer Killing Mechanisms 45 2.5.2 Imaging Immune Checkpoints Blockade 46 2.5.3 Role of Tumor-Associated Antigen Presenting Cells in T Cell Infiltration and Immunosuppression 48 2.6 Concluding Remarks 51 References 52 Chapter 3: Vascular Normalization, T Cell Trafficking and Anti-tumor Immunity 58 3.1 Introduction 60 3.2 Events in T Cell Trafficking 61 3.3 The Tumor Vasculature Blocks T Cell Trafficking into Solid Tumors 61 3.3.1 The Tumor Vasculature is Aberrant 61 3.3.2 Tumor Conditioning of the Endothelial Barrier 64 3.4 Tumor Vascular Remodeling 65 3.4.1 TNFα Therapy 66 3.4.2 Metronomic Chemotherapy 67 3.4.3 Anti-VEGF 68 3.4.4 Tyrosine Kinase Inhibitors 68 3.4.5 Tumor Blood Vessel-Associated Antigens (TBVA)-Targeted Vaccines 71 3.4.6 Chimeric Antigen Receptor (CAR) T Cells 73 3.4.7 Combination Therapy: Vascular Normalizing Agents and Immunotherapy 74 3.5 Summary 75 References 76 Chapter 4: Disruption of Anti-tumor T Cell Responses by Cancer-Associated Fibroblasts 84 4.1 Introduction 86 4.2 Definition: From Myofibroblasts to CAFs 87 4.3 On the Origin of CAFs 88 4.4 Role of CAFs on Non-immune Components of the Tumor 89 4.5 Influence of CAFs on Immune Components of Tumors 90 4.5.1 Role of CAFs on Innate Immune Components (Fig. 4.2) 90 4.5.2 Role of CAFs on Tumor Infiltrating T Cells 93 4.6 Targeting CAFs to Harness the Immune System Against Tumors 98 4.7 Conclusion 99 References 99 Chapter 5: Cancer-Associated Tertiary Lymphoid Structures, from Basic Knowledge Toward Therapeutic Target in Clinic 106 5.1 Introduction 108 5.2 Relationship Between Tumor-Associated TLS and T Cell Infiltrate 109 5.2.1 From Rudimental Lymphoid Aggregates to Fully Organized TLS 109 5.2.2 Cellular Composition of the TLS T-Cell Rich Areas 110 5.2.3 Impact of Tumor-Associated TLS on the Local Immune Microenvironment 112 5.2.4 Prognostic Value of Cells Homing in the TLS T Cell-Areas 113 5.3 Relationship Between TLS and B Cell Infiltrate 116 5.3.1 TLS as Sites for Development of Tumor Specific Humoral Immunity 117 5.3.2 The Various Ways TLS B Cells May Impact Anti-tumor Immunity 118 5.3.2.1 By the Production of Ab 118 5.3.2.2 By Presenting TAA to T Cells 120 5.3.2.3 By Producing Molecules Modulating the T Cell Response 120 5.3.3 Regulation of TLS Immune Function 121 5.4 Immunotherapies and TLS Development 122 5.4.1 TLS Neogenesis 122 5.4.2 Vaccination 123 5.4.3 Immune Checkpoints 124 5.5 Conclusions 125 References 125 Chapter 6: Homing Improvement: Boosting T Cell Trafficking for Cancer Immunotherapy 133 6.1 Introduction 134 6.1.1 Passive Immunotherapy: Therapeutic Antibodies with Direct Effects on Tumor Cells 135 6.1.2 Immunomodulatory Therapy: Antibodies that Modify Immune Responses 136 6.1.3 Active (Cellular) Tumor Immunotherapy 137 6.1.4 Dendritic Cell Tumor Immunotherapy 137 6.1.5 T Cell Tumor Immunotherapy: Boosting Endogenous Responses 138 6.1.6 T Cell Tumor Immunotherapy: Adoptive Cellular Immunotherapy (ACT) 139 6.1.7 Adoptive Cellular Immunotherapy Using TILs 139 6.1.8 Adoptive Cellular Immunotherapy Using CAR-Modified T Cells 140 6.2 Barriers to Cellular Tumor Immunotherapy 141 6.2.1 Identification and Prioritization of Tumor-Specific Antigens (TSA) 141 6.2.2 Generation and Persistence of Sufficient Tumor-Reactive T Cells 142 6.2.3 Safety: Integration-Related Transformation 142 6.2.4 Safety: Excessive Persistence 143 6.2.5 Safety: Off-Target Damage 144 6.2.6 Safety: Tumor Lysis Syndrome 144 6.2.7 Suppressive Tumor Microenvironment 145 6.2.8 Poor Homing to Tumors 146 6.2.9 T Cell Trafficking During Inflammation 146 6.2.10 T Cell Trafficking to Tumors 148 6.3 Strategies to Overcome Poor T Cell Migration to Tumors 148 6.3.1 Systemic Treatments 149 6.3.2 Tumor Modifications 150 6.3.3 Expressing Chemokine Receptors on T Cells 150 6.3.4 Boosting Integrin Function on T Cells 152 6.3.4.1 Integrin Transregulation in T Cells 152 6.3.5 Integrin Transregulation in Tumor Homing 154 6.3.6 Introducing Integrin Transregulation to Adoptive Cellular Immunotherapy 156 6.3.7 Considerations and Future Questions for Improving Homing 157 6.4 Summary 158 References 159 Chapter 7: Chemokines and T Cell Trafficking into Tumors: Strategies to Enhance Recruitment of T Cells into Tumors 168 7.1 Chemokines and Their Receptors 169 7.2 Chemokine and Chemokine Receptor Expression in Tumors 170 7.3 Accessory Roles of Chemokines in Cancer 170 7.4 Chemokines Mediate Recruitment of Pro- and Anti-­tumoral Cells to the Tumor 171 7.5 Barriers to Entry: Functional and Physical Obstacles to T Cell Infiltration into Tumors 172 7.6 Functional Barriers to T Cell Entry 173 7.7 Physical Barriers to T Cell Entry 173 7.8 Breaking Through the Barrier 175 7.9 Modifying T Cells in Order to Improve T Cell Homing to the Tumor 176 7.10 Conclusion 178 References 179 Chapter 8: Strategies to Enhance Migration and Persistence of Chimeric Antigen Receptor (CAR)-T Cells into Tumors 183 8.1 Introduction 184 8.2 CAR-T Cells and Solid Tumors 185 8.3 CAR-T Cells and Migration to Tumors 186 8.3.1 T-Cell Trafficking 187 8.3.2 CAR-T Cell and Extra Cellular Matrix (ECM) 188 8.4 Persistence of CAR-T Cells at the Tumor Site 188 8.4.1 CAR-T Cells and Inhibitory Molecules 189 8.4.2 CAR-T Cells and Inhibitory/Suppressive Cells 190 8.4.3 CAR-T Cells and Inhibitory Ligand 191 8.5 Concluding Remarks 192 References 193 Index 198 Front Matter....Pages i-viii Basic Rules of T Cell Migration....Pages 1-19 Regulation of Anti-tumor T Cell Migration and Function: Contribution of Real-Time Imaging....Pages 21-49 Vascular Normalization, T Cell Trafficking and Anti-tumor Immunity....Pages 51-76 Disruption of Anti-tumor T Cell Responses by Cancer-Associated Fibroblasts....Pages 77-98 Cancer-Associated Tertiary Lymphoid Structures, from Basic Knowledge Toward Therapeutic Target in Clinic....Pages 99-125 Homing Improvement: Boosting T Cell Trafficking for Cancer Immunotherapy....Pages 127-161 Chemokines and T Cell Trafficking into Tumors: Strategies to Enhance Recruitment of T Cells into Tumors....Pages 163-177 Strategies to Enhance Migration and Persistence of Chimeric Antigen Receptor (CAR)-T Cells into Tumors....Pages 179-193 Back Matter....Pages 195-199