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Table of Contents
Contributors xi
Principles of Cancer Immunobiology
Introduction George C. Prendergast Elizabeth M. Jaffee 3
Overview 3
Historical Background 3
Looking Ahead: Marrying Chemotherapy and Immunotherapy 5
Parts of the Book 6
References 8
Further Reading 8
Cancer Immunoediting: From Immune Surveillance to Immune Escape Ryungsa Kim 9
Introduction 10
Cancer Immune Surveillance 10
Cancer Immunoediting 19
Concluding Remarks 25
References 25
Immunosurveillance: Innate and Adaptive Antitumor Immunity Masahisa Jinushi Glenn Dranoff 29
Introduction 30
Innate Antitumor Responses 30
Innate Immune Cells 31
Adaptive Antitumor Responses 33
The Interplay of Innate and Adaptive Antitumor Immunity 38
Conclusion 39
References 39
Cytokine Regulation of Immune Tolerance to Tumors Ming O. Li Richard A. Flavell 43
Introduction 43
CytokineRegulation of Immune Tolerance to Tumors 45
Summary and Future Perspectives 55
References 56
Immunological Sculpting: Natural Killer Cell Receptors and Ligands David A. Sallman Julie Y. Djeu 63
Introduction 64
Activating Human NK Receptors 65
Inhibitory NK Receptors 72
The Ly49 Receptor Family 74
Immunotherapy Approaches 74
Conclusion 77
References 78
Further Reading 80
Immune Escape: Immunosuppressive Networks Shuang Wei Alfred Chang Weiping Zou 83
Introduction 83
Imbalance Between Mature DCs and Immature DCs 84
Imbalance Between Stimulatory and Inhibitory B7 Family Molecules 87
Imbalance Between Regulatory T Cells and Conventional T Cells 90
Concluding Remarks 92
References 92
Cancer Therapeutics
Cytotoxic Chemotherapy in Clinical Treatment of Cancer Rajesh Thirumaran George C. Prendergast Paul B. Gilman 101
Introduction 101
DNA-Damaging Agents 103
Antimetabolites 109
Antimitotics 112
Chemotherapy Regimens 113
References 115
Useful Web Sites 116
Targeted Therapeutics in Cancer Treatment Colin D. Weekes Manuel Hidalgo 117
Introduction 118
Cell Cycle 119
The MAPK Family 131
Challenges in the Clinical Development of Signal Transduction Inhibitors 136
References 140
Concepts in Pharmacology and Toxicology Richard A. Westhouse Bruce D. Car 149
Introduction 150
Concepts in Pharmacokinetics 151
Concepts in Toxicology 159
Clinical Concerns for Pharmacology and Safety 164
Conclusion 165
References 165
Further Reading 166
Cancer Immunotherapy: Challenges and Opportunities Andrew J. Lepisto John R. McKolanis Olivera J. Finn 167
Introduction 168
Prerequisites for Effective Cancer Immunotherapy: Identifying Tumor Antigens 168
Adoptive (\"Passive\") Immunotherapy 169
Active-Specific Immunotherapy: Vaccines 171
Cancer-Induced Immunosuppression Impinges on Immunotherapy 172
Cancer Immunotherapy in Mice Versus Humans 175
Immunotherapy and Cancer Stem Cells 176
Autoimmunity Resulting from Cancer Immunotherapy 176
Conclusion and Future Considerations 177
References 178
Cancer Vaccines Freda K. Stevenson Gianfranco Di Genova Christian Ottensmeier Natalia Savelyeva 183
Introduction 184
Tumor Antigens 185
Spontaneous Immunity to Cancer 187
Toleragenic Pressure on Immunity to Cancer 187
Immune Responses to Conventional Vaccines 189
Cancer Vaccine Strategies 194
DNA Vaccines 195
Challenges of Translation to the Clinic 199
Concluding Remarks 200
References 200
Further Reading 204
Targets and Tactics to Improve Cancer Immunotherapy by Defeating Immune Suppression
Immunotherapy and Cancer Therapeutics: Why Partner? Leisha A. Emens Elizabeth M. Jaffee 207
Introduction: Why Immunotherapy for Cancer? 208
Immune Tolerance and Suppression: Multiple Layers of Negative Control 209
T Cell Activation: A Rheostat for Tuning Immune Responses 212
Immune Modulation with Therapeutic Monoclonal Antibodies 219
Therapeutics that Mitigate the Influence of CD4[superscript +]CD25[superscript +] Tregs 222
Endocrine and Biologically Targeted Therapy 224
Conclusion 225
References 225
Immune Stimulatory Features of Classical Chemotherapy Robbert G. van der Most Anna K. Nowak Richard A. Lake 235
Introduction 236
Tumor Cell Death 236
Pathways to Immunogenicity 239
Chemotherapy and the Immune System 243
A Practical Partnership: Chemotherapy and Immunotherapy 246
Effects of Chemotherapy on Human Antitumor Immunity and Chemoimmunotherapy Clinical Trials 250
References 252
Dendritic Cells and Coregulatory Signals: Immune Checkpoint Blockade to Stimulate Immunotherapy Drew Pardoll 257
Regulation of T Cell Responses to Antigen 258
Regulatory T Cells 261
Immune Checkpoints in the Tumor Microenvironment 262
Monoclonal Antibodies that Interfere with Coinhibitory Receptors on T Cells 266
What Is the Most Effective Way to Use Checkpoint Inhibitors? 269
References 270
Regulatory T Cells in Tumor Immunity: Role of Toll-Like Receptors Rong-Fu Wang 277
Introduction 278
Immune Cells in Immunosurveillance and Tumor Destruction 278
TLRs and Their Signaling Pathways 279
TLRs in Innate Immunity, Inflammation, and Cancer Development 280
Tumor-Infiltrating Immune Cells in the Tumor Microenvironment 281
Molecular Marker for CD4[superscript +] Tregs 282
Antigen Specificity of CD4[superscript +] Tregs 282
Suppressive Mechanisms of Tregs 283
Functional Regulation of Tregs and Effector Cells by TLR Signaling 283
Implications for Enhancing Antitumor Immunity 284
Conclusion 285
References 285
Tumor-Associated Macrophages in Cancer Growth and Progression Alberto Mantovani Paola Allavena Antonio Sica 289
Introduction 289
Macrophage Polarization 290
Macrophage Recruitment at the Tumor Site 291
Tam Expression of Selected M2 Protumoral Functions 294
Modulation of Adaptive Immunity by Tams 296
Targeting Tams 297
Concluding Remarks 300
References 302
Tumor-Associated Myeloid-Derived Suppressor Cells Stephanie K. Bunt Erica M. Hanson Pratima Sinha Minu K. Srivastava Virginia K. Clements Suzanne Ostrand-Rosenberg 309
Introduction 310
Multiple Suppressive Mechanisms that Contribute to Immunosuppression in Individuals with Tumors 310
MDSCs as a Key Cell Population that Mediates Tumor-Induced Immunosuppression 311
MDSCs\' Use of Mechanisms to Mediate Effects on Multiple Target Cells 317
MDSC Induction by Tumor-Derived Cytokines and Growth Factors 321
MDSC Linking of Inflammation and Tumor Progression 322
Agents Responsible for Reducing MDSC Levels 323
Conclusions: Implications for Immunotherapy 326
References 327
Further Reading 331
Programmed Death Ligand-1 and Galectin-1: Pieces in the Puzzle of Tumor-Immune Escape Gabriel A. Rabinovich Thomas F. Gajewski 333
Programmed Death Ligand 1 and Programmed Death 1 Interactions 334
Galectin 1 338
References 344
Further Reading 346
Indoleamine 2,3-Dioxygenase in Immune Escape: Regulation and Therapeutic Inhibition Alexander J. Muller George C. Prendergast 347
Introduction 348
IDO Function in T Cell Regulation 351
Complex Control of IDO by Immune Regulatory Factors 351
Immune Tolerance Via IDO in Dendritic Cells 353
IDO Dysregulation in Cancer Cells 357
IDO as a Target for Therapeutic Intervention 359
Discovery and Development of IDO Inhibitors 360
Conclusion 361
References 362
Further Reading 368
Arginase, Nitric Oxide Synthase, and Novel Inhibitors of L-Arginine Metabolism in Immune Modulation Susanna Mandruzzato Simone Mocellin Vincenzo Bronte 369
Introduction 370
NOS: Genes, Regulation, and Activity 371
ARG: Genes, Regulation, and Activity 372
Immunoregulatory Activities of ARG and NOS 374
Possible Physiological Role for L-ARG Metabolism in Immunity Control 381
NOS in Cancer 382
ARG in Cancer 384
ARG and NOS Inhibitors: A Novel Class of Immune Adjuvants? 386
Conclusion and Perspectives 388
References 389
Further Reading 399
Index 401