Dendritic Cells in Cancer (eBook)

Dendritic Cells in Cancer 2
Preface 5
Contents 6
Contributors 9
Introduction 15
The Central Role of Dendritic Cells in Immunity 16
1.1 Dendritic Cell Subsets 16
1.2 Dendritic Cells: Antigen Uptake and Processing 17
1.3 Dendritic Cell Activation and Maturation 19
1.4 Dendritic Cells in Directing T-Cell Responses 20
1.5 Tolerogenic Dendritic Cells 21
1.6 Conclusion 22
References 23
Dendritic Cells in Cancer: Emergence of the Discipline 26
2.1 Discovery of Dendritic Cells 26
2.2 Dendritic Cells in Cancer: Recognition of Their Functional Significance 28
2.3 Dendritic Cells in Cancer: Recognition of Their Role in Tumor Escape 32
2.4 Dendritic Cells in Cancer: Recognition of the Diversity of Regulatory Roles 35
References 37
Part 1: Alterations of the Dendritic Cell System in Cancer 46
Tumor-Infiltrating Dendritic Cells: The Pathologist’s Perspective 47
3.1 Dendritic Cells at the Tumor Site: Introduction 47
3.2 TIDC: Technical Aspects 49
3.3 TIDC in Head and Neck Malignancy 51
3.4 TIDC in Digestive System Malignancy 53
3.5 TIDC in Pulmonary Malignancy 54
3.6 TIDC in Genitourinary Malignancy 55
3.7 TIDC in Breast Carcinoma 56
3.8 TIDC in Gynecologic Malignancy 56
3.9 TIDC in Malignant Melanoma 57
3.10 TIDC in Pediatric Malignancy 58
3.11 Conclusions 58
3.12 Future Directions 61
References 62
Functional Defects of Dendritic Cells in Cancer 70
4.1 Introduction 70
4.2 Uptake and Processing of Antigens 72
4.3 Migration 73
4.4 Maturation, Antigen Presentation and Co-Stimulation 75
4.5 Cytokine Production 78
4.6 Concluding Remarks 80
References 81
General Properties of Dendritic Cell Populations in Cancer 89
5.1 Introduction 89
5.2 Factors Affecting Dendritic Cell Distribution in the Tumor Microenvironment 90
5.3 Factors Affecting Dendritic Cell Function in the Tumor Microenvironment 91
5.4 Characteristics of Tumor Microenvironmental Dendritic Cells 91
5.5 Strategies to Improve Tumor Microenvironmental Dendritic Cell Numbers or Function 93
5.6 Murine Tumor Models to Study Plasmacytoid Dendritic Cells in Cancer 93
5.7 Human Cancers Amenable to Studies of Microenvironmental Dendritic Cells 94
5.8 Conclusions 95
References 95
Elimination of Dendritic Cells in Cancer 100
6.1 Introduction 100
6.2 Blockage of Dendritic Cell Generation and Maturation 102
6.3 Induction of Apoptosis in Dendritic Cells and Their Precursors 103
6.4 Conclusions 106
References 106
Part 2: Mechanisms of Dendritic Cell Dysfunction in Cancer 111
Tumor-Derived Factors Responsible for Dendritic Cell Dysfunction 112
7.1 Introduction 112
7.2 Cytokines and Growth Factors Affecting Dendritic Cell Differentiation 113
7.3 Other Immune Mediators Affecting Dendritic Cell Differentiation 114
7.4 Tumor Antigens and Metabolites Affecting Dendritic Cell Differentiation 117
7.5 Implications of Altered Dendritic Cell Differentiation 117
7.6 Tumor-Derived Factors and Dendritic Cell Apoptosis 119
7.7 Concluding Remarks 120
References 121
Tumor-Derived Exosomes as Dendritic Cell Modulators 127
8.1 Introduction 128
8.2 Tumor-Derived Exosomes Immunophenotype 128
8.3 Tumor-Derived Exosomes and the Induction of Dendritic Cell-Mediated Antigen Cross-Presentation 130
8.4 Tumor-Derived Exosomes and the Impairment of Dendritic Cell Differentiation 131
8.5 Driving the Interaction Between Tumor-Derived Exosomes and Dendritic Cells Toward Immune Stimulation: Is It Possible? 133
References 134
Signaling Pathways Mediating Dendritic Cell Dysfunction in Cancer 137
9.1 Introduction 137
9.2 MAPK-Signaling Pathways 138
9.3 p38 MAPK in Dendritic Cell Differentiation, Maturation, and Activity 139
9.4 p38 MAPK in Tumor-Induced Dendritic Cell Dysfunction 140
9.5 ERK and Dendritic Cell Dysfunction in Cancer 142
9.6 Role of JAK/STAT Signaling in Tumor-Induced Dendritic Cell Dysfunction 142
9.7 Other Signaling Pathways in Tumor-Induced Dendritic Cell Dysfunction 143
9.8 Conclusion 144
References 145
A Role for STAT3 in Dendritic Cell Regulation by Tumor-Derived Factors 151
10.1 Introduction 151
10.2 Overview of Jak/STAT Pathway 152
10.3 Jak/STAT Signaling in Dendritic Cell Differentiation and Function 154
10.4 Jak/STAT3 and Abnormal Dendritic Cell Differentiation and Maturation in Cancer 157
10.5 Targeting Jak/STAT Pathway in Dendritic Cells 158
10.6 Conclusions 160
References 160
Tumor-Associated Inflammation and Impact on Dendritic Cell Function 164
11.1 Introduction: Tumor-Associated Inflammation 165
11.2 Inflammation and Dendritic Cell Functions in the Proto-cancer 166
11.3 Inflammation and Dendritic Cell Functions in Established Tumors 168
11.4 Inflammation and Dendritic Cell Functions During Rejection of Established Tumors 170
11.5 Inflammation and Dendritic Cell Function in Terminal Phase Cancer Ultimately Escaping Immune Control 173
11.6 Summary 174
References 174
Changes in Dendritic Cells in Cancer and Aging 178
12.1 Introduction 178
12.2 Age-Associated Alterations in Dendritic Cell Function 179
12.2.1 Dendritic Cell Numbers in Old Age 179
12.2.2 Differentiation and Maturation of DC in Old Age 180
12.2.3 Antigen Uptake in the Aged 181
12.2.4 DC Migration in Old Age 181
12.2.5 T-Cell Stimulatory Properties in Old Age 182
12.3 Consequences of the Senescence of Dendritic Cells in Cancer Immunotherapy 183
12.4 Conclusions 185
References 185
Stress, Immunity and Dendritic Cells in Cancer 188
13.1 Psychosocial Factors and Health 188
13.2 Stress, Homeostasis and Allostatic Load 190
13.3 Stress and the Immune System: An Overview 192
13.4 Stress and Dendritic Cells 194
13.5 Effects of Psychological Stress on Dendritic Cell Function 194
13.6 Mechanisms of Stressor-Induced Modulation of Dendritic Cell Function 197
13.6.1 Glucocorticoids 198
13.6.2 Role of the Sympathetic Nervous System: Norepinephrine 199
13.7 Concluding Comments 200
References 201
Cancer Therapy and Dendritic Cell Immunomodulation 207
14.1 Modulation of Dendritic Cell Activity by Surgical Procedures 207
14.2 Impact of Radiation Therapy on Dendritic Cells 210
14.3 Regulation of Dendritic Cell Function by Chemotherapy: Impact of High- Versus Low-Dose Chemotherapy on Dendritic Cell Activity 212
14.4 Chemomodulation of Small Rho GTPase Activity in Dendritic Cells 215
14.5 Chemomodulation of Cytokine Expression in Dendritic Cells 215
14.6 Conclusions 217
References 217
Part 3: Role of Dendritic Cells in Tumor Escape 223
Role of IDO in Dendritic Cell Differentiation and Function in Cancer 224
15.1 IDO - A Tryptophan-Catabolizing Enzyme with Immunoregulatory Properties 224
15.2 Mechanisms of IDO-Mediated Suppression: Tryptophan Starvation and Downstream Metabolite Toxicity 226
15.3 Induction of IDO in Dendritic Cells 228
15.4 IDO-Mediated Dendritic Cell-Driven Immune Suppression in the Tumor Environment 229
15.5 IDO Inhibitors and Their Role in Dendritic Cell-Targeted Cancer Immunotherapy 230
15.6 Role of IDO in Dendritic Cell Differentiation and Function 230
References 231
Dendritic Cells: From Inducers of Specific T-Cell Responses to Promoters of Angiogenesis 235
16.1 Dendritic Cells in Mouse and Humans 235
16.2 Dendritic Cell Maturation Process 236
16.3 Dendritic Cells with Immunosuppressive Properties in the Tumor Microenvironment 237
16.4 Dendritic Cells Showing Endothelial Cell Properties 238
16.5 Dendritic Cells as a Source of Angiogenic Factors 239
16.6 Angiogenic Properties of Mature Dendritic Cells 241
16.7 Final Comments 241
References 241
Protumorigenic Function of Dendritic Cells 246
17.1 Introduction 246
17.2 Role of Dendritic Cells in the Tumor Microenvironment 247
17.3 Protumorigenic Effects of Dendritic Cells 248
17.3.1 DC and Enhanced Tumor Growth 248
17.3.2 DC and Immunosuppression 249
17.3.3 DC and Angiogenesis 250
17.3.4 Transdifferentiation of DC 251
17.3.5 DC and Metastasis 252
17.4 Dendritic Cells Versus Macrophages 252
17.5 Summary 253
References 254
Dendritic Cell Maturation Versus Polarization in Tumor Escape 260
18.1 Introduction 260
18.2 Tumor Manipulation of Dendritic Cell Biology 261
18.3 ‘‘Entry’’ Level Deviation of Dendritic Cells by Tumors 261
18.4 Instruction Lost 264
18.5 Tumor Microenvironment-Associated Deviation of Dendritic Cell/T-Cell Functional Polarization 265
18.6 Conclusions 266
References 267
Part 4: Dendritic Cells in Cancer: Clinical Aspects 272
Trafficking of Dendritic Cells in the Tumor Environment 273
19.1 Regulation of Dendritic Cell Trafficking: Introduction 273
19.2 Trafficking of Dendritic Cells at the Tumor Site 276
19.3 Dendritic Cell Vaccines and Dendritic Cell Trafficking in Cancer 279
19.4 Intratumoral Dendritic Cell Vaccines 281
19.5 Conclusions 284
References 284
Dendritic Cells in Tumor-Draining Lymph Nodes 292
20.1 Normal Physiologic Flow of Dendritic Cells to Lymph Nodes 292
20.2 Heterogeneity of Immune Reactivity from Node to Node 295
20.3 Sentinel Node Concept 296
20.4 Alterations in Dendritic Cell Number, Phenotype and Activation Status 296
20.5 Molecular and Signaling Alterations in the Sentinel Lymph Nodes 298
20.6 Reversal of Immunomodulation of the Sentinel Lymph Nodes: A Novel Adjuvant Therapeutic Option? 300
References 302
Dendritic Cell Vaccines in Cancer: Obstacles to Overcome 309
21.1 Introduction 309
21.2 Use of Dendritic Cell Subsets for Immunotherapy 310
21.3 Generation of Dendritic Cells for Therapeutic Vaccines 312
21.4 Antigen Selection for Therapeutic Vaccination 315
21.5 Optimizing Conditions for Antigen Loading 316
21.6 Enhancing Immune Responses to Dendritic Cell Vaccination 318
21.7 Routes, Dose, and Timing of Vaccine Administration 320
21.8 Evaluating Efficacy of Dendritic Cell Vaccines 321
21.9 Conclusion 322
References 323
How Best to Generate Dendritic Cells from Patients with Cancer and How Best to Use them for Immunotherapeutic Purposes 331
22.1 Naturally Occurring and Ex Vivo-Generated Dendritic Cells 331
22.2 Dendritic Cell Generation for Clinical Trials 333
22.3 Quality Control Required for Dendritic Cell Produced for Immunotherapy 334
22.3.1 Purity 334
22.3.2 Sterility 334
22.3.3 Viability 334
22.3.4 Maturation 335
22.3.5 Stability 335
22.3.6 Potency 335
22.4 Dendritic Cell Vaccines in Specific Cancers: In vitro and In vivo Assessment 336
22.4.1 Esophageal Carcinoma 336
22.4.2 Gastric Carcinoma 336
22.4.3 Cholangiocarcinoma 337
22.4.4 Pancreatic Carcinoma 338
22.4.5 Hepatocellular Carcinoma (HCC) 338
22.4.6 Colorectal Carcinoma (CRC) 339
22.5 Future Directions 340
References 341
Genetically Modified Dendritic Cells in Cancer Immunotherapy 347
23.1 Introduction 347
23.2 Genetic Modification of Dendritic Cells 348
23.3 Pre-clinical Models of Genetically Modified Dendritic Cell Vaccines 350
23.4 Genetically Modified Dendritic Cell Vaccines in Clinical Trials 352
23.5 Strategies for Increasing Efficacy of Genetically Modified Dendritic Cell Vaccines 357
23.6 Conclusions 359
References 360
Dendritic Cell Tumors 364
24.1 Origin and Classification of Dendritic Cell Tumors 364
24.2 Follicular Dendritic Cell Tumor/Sarcoma 365
24.2.1 Gross Features and Histomorphology 366
24.2.2 Clinical Behavior and Outcome 367
24.3 Interdigitating Dendritic Cell Tumor/Sarcoma 368
24.3.1 Gross Features and Histomorphology 368
24.3.2 Clinical Behavior and Outcome 368
24.4 Langerhans Cell Histiocytosis/Sarcoma 370
24.4.1 Gross Features and Histomorphology 370
24.4.2 Clinical Behavior and Outcome 370
24.5 Conclusions 372
References 372
Future Directions in Dendritic Cell Research in Cancer 374
25.1 Location, Location, Location 375
25.2 Function and Plasticity 376
25.3 Dendritic Cells as a Focal Point for Immune Regulation 377
25.4 Harnessing Dendritic Cells for Immune Therapy of Cancer 378
25.4.1 Ex Vivo Dendritic Cell Vaccines 378
25.4.2 In-Situ Dendritic Cell Targeting 379
25.5 Summary 379
References 380
Index 383