Innate and Adaptive Immunity in the Tumor Microenvironment (eBook)

Foreword 5
Tumor Microenvironment under the Magnifying Glass: A New Challenge to Cancer Immunologists 5
Contents 9
List of Contributors 11
Immune Effector Cells in the Tumor Microenvironment 13
1.1 Introduction 13
1.2 Evidence for Loco-regional Immune Dysfunction in Cancer 15
1.2.1 Biologic Significance of Loco-regional Immune Suppression 16
1.3 Evidence for Systemic Immune Deviation in Cancer 17
1.4 Mechanisms Responsible for Dysfunction of Immune Cells in Cancer Patients 17
1.4.1 Interference with the Induction of TAA-specific Responses 18
1.4.2 Interference with Functions/Survival of Effector T Lymphocytes 23
1.4.3 A loss of Tumor Recognition by Immune Cells 28
1.4.4 Resistance of Tumor Cells to Immune Intervention 31
1.4.5 Tumor-derived Suppressive Factors 33
1.5 Conclusions 33
References 34
Histocompatibility Antigens, Tumor Microenvironment and Escape Mechanisms Utilized by Tumor Cells 46
2.1 Introduction 46
2.2 Classical and Non-Classical HLA Class I Antigens and NK- Cell Activating Ligands in Malignant Lesions 47
2.3 Antigen Presentation by HLA Class I Antigens 50
2.4 Modulation of APM Components by Cytokines in the Tumor Microenvironment 52
2.4.1 IL-10 53
2.4.2 Transforming Growth Factor-b (TGF-b) 54
2.4.3 Interferon-g (IFN-g ) 55
2.5 Potential Effects of Released Classical and Non-Classical HLA Class I Antigens and NK- Cell Activating Ligands in the Tumor Microenvironment 56
2.6 Conclusions 57
References 59
Local Tumor Growth and Spontaneous Systemic T Cell Responses in Cancer Patients: A Paradox and Puzzle 63
3.1 Introduction 63
3.2 Spontaneous T Cell Immunity and the Tumor Microenvironment 64
3.2.1 Spontaneous Systemic T Cell Responses in Cancer Patients 64
3.2.2 The Bone Marrow as a Source of Tumor-reactive T Cells 66
3.2.3 Systemic T Cell Immunity and T Cell Entry into Tumor Tissue 69
3.2.4 The Tumor Microenvironment and the Induction and Function of Tumor Specific T Cells 71
3.3 Intervention in Tumor Microenvironment 75
3.3.1 Counteracting Immune Deregulation 75
3.3.2 Counteracting Metabolic Deregulation 78
3.3.3 Intervention by Physical Means: Radiation, Hyperthermia, Electrochemical Therapy 78
3.3.4 Intra-Tumoral Delivery of Viral Vectors or Slow- release Systems 79
3.3.5 Locoregional Interference Via Port Systems 80
3.4 Future Directions 80
References 81
Insights into Mechanisms of Immune Resistance in the Tumor Microenvironment through Molecular Profiling 87
4.1 Introduction 87
4.2 Melanoma Microenvironment Analysis Through Gene Expression Profiling 88
4.3 Regulation of Migration into Tumor Metastases 89
4.4 Inhibitory Mechanisms in the Tumor Microenvironment 91
4.5 Resistance at the Level of the Tumor Cells Themselves 94
4.6 Relevance of Understanding the Melanoma Microenvironment to Immunotherapy Clinical Trials 94
References 96
Tumor Antigens as Modulators of the Tumor Microenvironment 100
5.1 Introduction 100
5.2 Mr. Hyde MUC1 Promotes Tumorigenesis 102
5.3 Dr. Jekyll MUC1 is a Tumor Antigen Targeted by Immune Surveillance 103
5.4 Mr. Hyde MUC1 Manipulates Tumor Microenvironment 105
5.5 Other Dr. Jekyll and Mr. Hyde-Like Tumor Antigens 106
5.5.1 Dr. Jekyll CEA 106
5.5.2 Mr. Hyde CEA 108
5.5.3 Dr. Jekyll Tumor Glycolipids 108
5.5.4 Mr. Hyde Tumor Glycolipids 109
5.5.5 Dr. Jekyll gp100 110
5.5.6 Mr. Hyde gp100 110
5.6 Cancer Stem Cells and their Dr. Jekyll and Mr. Hyde Antigens 111
5.7 Candidate Cancer Stem Cell Markers 112
5.8 The Stem Cell Niche as the Tumor Microenvironment 114
5.9 Signaling Pathways that Control Cancer Stem Cell Function 115
5.10 Cancer Stem Cell Antigens and the Tumor Microenvironment 115
5.11 Targeting Tumor Antigens to Change Tumor Microenvironment and Restore Immunosurveillance 117
Abbreviations 118
References 118
Tumor Cell Resistance to Apoptosis by Infiltrating Cytotoxic Lymphocytes 129
6.1 Introduction 130
6.2 Apoptosis as a Cytotoxic Mechanism Induced by Cytotoxic Lymphocytes 131
6.3 Inhibition of Apoptosis as a Mechanism of Cross Resistance 132
6.4 Mechanisms of Resistance to Cytotoxic Immune Cells 132
6.4.1 Extrinsic 132
6.4.2 Intrinsic 133
6.5 Sensitization of Resistant Tumor Cells to Cytotoxic Lymphocytes/ Factors- mediated Apoptosis 134
6.5.1 Chemosensitizing Drugs as Immunosensitizing Agents 134
6.5.2 Nitric Oxide (NO) Donors as Immunosensitizing Agents 136
6.5.3 Antibody-mediated Immunosensitization 137
6.5.4 Pharmacologic Inhibitors 137
6.6 Influence of the Tumor Microenvironment on the Development of Tumor Cell Resistance to Cytotoxic Therapy 138
6.7 Therapeutic Implications 139
6.8 Concluding Remarks 139
References 140
The Tumor Microenvironment as a Model for Tissue- Specific Rejection 146
7.1 Introduction 146
7.1.1 Innate Immunity and Inflammation 150
7.1.2 Dendritic Cells 150
7.1.3 NK Cells 151
7.1.4 T Cells 152
7.1.5 Tumor Cells 155
References 156
Functional Cytotoxicity of T Cells in the Tumor Microenvironment 163
8.1 Introduction 163
8.2 Early Events: Antigen Presentation, CTL Activation and Migration 164
8.3 The Immune Synapse 165
8.4 Functional CTL Capture Membrane Fragments from Tumors 166
8.5 Killing Mechanisms of CTLs 169
8.5.1 Cytotoxins 169
8.5.2 Cytokines 170
8.5.3 Membrane-associated Proteins 170
8.6 Future Research Directions to Improve Functional Cytotoxicity of Tumor- specific CTLs 171
References 172
Natural Killer Cells at the Tumors Microenvironment 177
9.1 Introduction 177
9.2 Basic Properties of Natural Killers 177
9.3 The Presence of NK Cells Inside Tumors 178
9.4 Trafficking to the Tumor Site 179
9.5 Innate Recognition of Tumor Cells 180
9.6 Modulation of Tumor Recognition by NK Cells 181
9.7 MHC Class-I Independent Inhibition of NK Cells 183
9.8 Effector Functions and Tumor Development 183
9.9 TNF Family Ligands 184
9.10 The Influence of Physico-chemical Microenvironment on NK Cells 185
9.11 IL-10 186
9.12 TGF-ß 186
9.13 NK–DCs Interactions 187
9.14 Suppression of NK by Immune-regulatory Cells 188
9.15 Killing of Metastatic Cancerous Cells by NK 189
9.16 Concluding Remarks 189
References 189
Contribution of the Microenvironment to the Pathogenesis of EBV- Positive Hodgkin and Nasal NK/ T- cell Lymphomas 200
10.1 Background 200
10.2 Expression of EBV-encoded Proteins in Lymphocytes with Latent Infection 202
10.3 The Changes of Viral Expression Concomitant with B- cell Maturation 203
10.4 EBV-carrying Hematopoetic Malignancies with Type IIa Restricted Viral Gene Expression 204
10.4.1 Hodgkin lymphoma, HL 205
10.4.2 Extranodal, Nasal NK/T-cell Lymphoma 208
10.5 Conclusion 210
References 211
Index 215