Dranoff Cancer Immunology and Immunotherapy

1. Auflage 2011
ISBN: 978-3-642-14136-2
Verlag: Springer
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, Band 344, 306 Seiten

Reihe: Current Topics in Microbiology and Immunology

The interplay between tumors and their immunologic microenvironment is complex, difficult to decipher, but its understanding is of seminal importance for the development of novel prognostic markers and therapeutic strategies. The present review discusses tumor-immune interactions in several human cancers that illustrate various aspects of this complexity and proposes an integrated scheme of the impact of local immune reactions on clinical outcome. Current active immunotherapy trials have shown durable tumor regressions in a fraction of patients. However, clinical efficacy of current vaccines is limited, possibly because tumors skew the immune system by means of myeloid-derived suppressor cells, inflammatory type 2 T cells and regulatory T cells (Tregs), all of which prevent the generation of effector cells. To improve the clinical efficacy of cancer vaccines in patients with metastatic disease, we need to design novel and improved strategies that can boost adaptive immunity to cancer, help overcome Tregs and allow the breakdown of the immunosuppressive tumor microenvironment.

Autoren/Hrsg.

Dranoff, Glenn

Inhaltsverzeichnis

1;Preface;6
1.1;References;7
2;Contents;8
3;Contributors;10
4;Immune Infiltration in Human Cancer: Prognostic Significance and Disease Control;16
4.1;1 Introduction;17
4.2;2 ``In Situ´´ Immune Contexture, the Strongest Prognostic Factor for Recurrence and Overall Survival: The Case of Colorectal Cancer;19
4.3;3 Induction of Functionally Active Tertiary Lymphoid Structures in the Vicinity of Tumoral Beds as Potential Sites of ``In Situ Immune Reactions: The Example ofLung Carcinoma;23
4.4;4 Subversion of Innate Immunity Receptors: Stimulation of Toll Like Receptors on Lung Carcinoma Cells Modulates Cell Survival and Response to Chemotherapy;26
4.5;5 ``Paradoxical´´ Control of Inflammation Influences Clinical Outcome in Head and Neck Cancer;28
4.6;6 The Immune Reaction in a Tumor Developing in an Immuno-Priviledged Site: The Case of Primary Intraocular Lymphoma;31
4.7;7 Conclusions;33
4.8;References;34
5;Subversion and Coercion: The Art of Redirecting Tumor Immune Surveillance;40
5.1;1 Introduction;41
5.2;2 The Inflammatory Trio: TNF-a, TGF-beta, IL-6;43
5.3;3 The Local Trigger: IL-23 and IL-12 Balance in the Tumor Microenvironment;45
5.4;4 Feeding the Inflammatory Niche: Adaptive T Cell Responses Fostering the Tumor;46
5.5;5 Turning Foes into Friends, CD8+ T Cells Lose Their Teeth;47
5.6;6 Inflammatory Control at the Tumor Site;48
5.7;7 Conclusions;50
5.8;References;51
6;STAT3: A Target to Enhance Antitumor Immune Response;55
6.1;1 Introduction;56
6.2;2 Stat3-Mediated Immune Suppression;57
6.2.1;2.1 Inhibition of the Th1 Immune Response;57
6.2.2;2.2 Relevant Immunologic Signaling Pathways;59
6.2.3;2.3 Role in Myeloid Derived Suppressor Cells;60
6.2.4;2.4 Role in Regulatory T-Cells;61
6.3;3 Therapeutic Relevance;62
6.3.1;3.1 Genetic Evidence and Potential Toxicity;63
6.3.2;3.2 JAK Inhibitors;63
6.3.3;3.3 Other Oncogenic Kinase Inhibitors;64
6.3.4;3.4 RTK Inhibitors;65
6.3.5;3.5 siRNA;66
6.4;4 Concluding Remarks;67
6.5;References;67
7;Biology and Clinical Observations of Regulatory T Cells in Cancer Immunology;74
7.1;1 Introduction;76
7.2;2 Treg Lineage and Development;76
7.3;3 Treg Subsets;77
7.3.1;3.1 Cell Surface Markers of Mouse Tregs;77
7.3.2;3.2 Cell Surface Markers of Human Tregs;78
7.3.3;3.3 Toll Like Receptors Expressed by Tregs;79
7.3.4;3.4 Functional Subsets of Tregs;79
7.3.5;3.5 Treg-Derived Malignancies;80
7.4;4 Mechanisms of Treg-Mediated Immune Suppression in Cancer;80
7.4.1;4.1 Immunosuppressive Cytokines and Factors;81
7.4.2;4.2 Suppression by Direct Cell-Cell Contact;81
7.4.3;4.3 Treg-Mediated Cytotoxicity;82
7.5;5 Clinical Observations of the Association of Tregs with Cancer;82
7.6;6 Modification of Treg Biology as Cancer Immunotherapy;90
7.6.1;6.1 The Cellular Microenvironment;90
7.6.2;6.2 Strategies to Modulate Treg Number and Function;92
7.6.3;6.3 Attenuating Treg Function;93
7.7;7 Conclusions;96
7.8;References;96
8;Concepts and Ways to Amplify the Antitumor Immune Response;109
8.1;1 Introduction;110
8.2;2 Pharmacology of Tumor Cell-Immune Cell Interactions;112
8.3;3 Tumor Cell Development and Its Danger Signals;113
8.3.1;3.1 Neoplastic Cells;114
8.3.2;3.2 Chronic Inflammation;115
8.3.3;3.3 Stroma;117
8.4;4 Expression and Presentation of Tumor Antigens;117
8.5;5 Mouse Models of Cancer;119
8.5.1;5.1 The LCMV Model to Study the Regulation of MHCI Expression;119
8.5.2;5.2 The L12R4 Vaccination Model;121
8.5.3;5.3 The SR/CR Mouse Model;122
8.6;6 Cellular and Molecular Regulation of Tumor Immunity;125
8.7;7 Discussion;129
8.8;References;134
9;Angiogenesis and the Tumor Vasculature as Antitumor Immune Modulators: The Role of Vascular Endothelial Growth Factor and Endothelin;141
9.1;1 Introduction;142
9.2;2 Angiogenesis and Cancer;143
9.3;3 Vascular Endothelial Growth Factor;144
9.4;4 Direct Effects of VEGF on Leukocytes;145
9.4.1;4.1 Dendritic Cell Defects in Cancer Patients and Mouse Models: A Role for VEGF;145
9.4.2;4.2 Effects of VEGF on T Cells;147
9.5;5 VEGF, the Tumor Vascular Endothelium, and Immune Evasion;149
9.5.1;5.1 The Vascular Endothelium;149
9.5.2;5.2 VEGF and Adhesion Molecule Expression;149
9.6;6 The Tumor Endothelium and VEGF Crosstalk: A Role for the Endothelin System;150
9.6.1;6.1 The Endothelin System;150
9.6.2;6.2 Endothelin and Tumor Angiogenesis;151
9.6.3;6.3 ETBR and the Tumor Endothelial Barrier to T Cell Homing;152
9.7;7 Concluding Statements;153
9.8;References;154
10;Adoptive Cellular Therapy;161
10.1;1 Introduction;162
10.2;2 Finding the Right Tool for the Job;163
10.3;3 Considerations of Cell Culture Technology;165
10.3.1;3.1 General Approaches for Cell Manufacturing;166
10.3.2;3.2 Artificial APC;167
10.3.3;3.3 Moving to the Dark Side: Culture Systems for Tregs;168
10.4;4 Engineering T Cells;169
10.4.1;4.1 Introduction of Transgenic TCRs;169
10.4.2;4.2 Creation of MHC-Independent T Cells with Chimeric Antigen Receptors;170
10.4.3;4.3 Issues Facing the Field with Gene-Modified ACT;171
10.5;5 Post-Transplant ACT;172
10.5.1;5.1 ACT for Hematologic Malignancies;174
10.5.2;5.2 ACT for Neuroblastoma;176
10.6;6 Concluding Remarks;177
10.7;References;178
11;Dendritic Cell Subsets as Vectors and Targets for Improved Cancer Therapy;185
11.1;1 Introduction;186
11.2;2 Dendritic Cells;187
11.2.1;2.1 Human Dendritic Cell Subsets;187
11.2.1.1;2.1.1 Dermal DCs, Antibody Responses and IL-12;187
11.2.1.2;2.1.2 LCs and CD8+ T Cell Responses;189
11.2.1.3;2.1.3 Plasmacytoid DCs;189
11.2.2;2.2 DCs in Tumor Environment;190
11.3;3 Dendritic Cells in Vaccination Against Cancer;192
11.3.1;3.1 Outcomes of Current DC Vaccination Trials;192
11.3.2;3.2 The Quality of Elicited Antigen-Specific Immune Responses;192
11.4;4 Building on Dendritic Cell Subsets to Improve Cancer Vaccines;193
11.4.1;4.1 Optimal DCs;193
11.4.2;4.2 ``Ideal´´ Antigens;194
11.4.3;4.3 Combining DC Vaccines with Other Therapies;195
11.5;5 Concluding Remarks;197
11.6;References;198
12;Identification of Human Idiotype-Specific T Cells in Lymphoma and Myeloma;205
12.1;1 Introduction;206
12.2;2 Idiotype Protein as a Tumor Antigen: Discovery Research;206
12.3;3 Clinical Investigational New Drug Vaccine Development;207
12.4;4 Pivotal Phase III Trials;207
12.5;5 Idiotype-Specific T Cell Immunity Elicited by Idiotype Vaccination in Preclinical Models;209
12.6;6 Human T Cell Epitopes Identified in Lymphoma-Derived Idiotype Proteins;211
12.7;7 Ig Light-Chain as a Source of Idiotype Peptide Recognized by Human T Cells;213
12.8;8 Future Directions for Idiotype-Specific T Cell Immunotherapy;216
12.9;References;218
13;Modulation of CTLA-4 and GITR for Cancer Immunotherapy;223
13.1;1 Introduction;224
13.2;2 CTLA-4 Preclinical Data;225
13.2.1;2.1 CTLA-4: A ``Brake´´ on T Cell Activation;226
13.2.1.1;2.1.1 Cell Intrinsic Suppression;227
13.2.1.2;2.1.2 Cell Extrinsic Suppression;227
13.2.2;2.2 Preclinical Studies Using CTLA-4 Blocking Antibodies;229
13.2.2.1;2.2.1 Monotherapy;229
13.2.2.2;2.2.2 CTLA-4 and Active/Passive Immunization;229
13.2.2.3;2.2.3 CTLA-4 and Chemotherapy/Radiotherapy/Tumor Ablation;230
13.2.2.4;2.2.4 CTLA-4 and Other Immunostimulatory Strategies;230
13.3;3 GITR Preclinical;231
13.3.1;3.1 GITR: ``Accelerator´´ of Effector Function;232
13.3.2;3.2 Preclinical Studies Using GITR Agonist Antibody;232
13.3.2.1;3.2.1 Monotherapy;233
13.3.2.2;3.2.2 GITR and Active Immunization;233
13.4;4 Clinical Experiences with CTLA-4 Blockade;234
13.4.1;4.1 CTLA-4 Monotherapy;235
13.4.2;4.2 Postsurgical Adjuvant Therapy;237
13.4.3;4.3 Combinations;238
13.4.4;4.4 Tremelimumab;238
13.4.5;4.5 Immune Related Adverse Effects;239
13.4.6;4.6 Novel Criteria for Antitumor Response to Ipilimumab and Increased Duration of Response;239
13.4.7;4.7 Other Malignancies;240
13.5;5 From Clinical Trials, Back to the Bench;241
13.5.1;5.1 Monitoring Antigen-Specific CD4+ and CD8+ T Cell Activity and Polyfunctionality;241
13.5.2;5.2 Cellular Phenotype Analysis: ICOS, Foxp3, HLA-DR and IDO;242
13.5.3;5.3 ICOS;243
13.5.4;5.4 Foxp3;243
13.5.5;5.5 HLA-DR;243
13.5.6;5.6 IDO;244
13.5.7;5.7 Antibody Responses;244
13.5.8;5.8 The ``Immunogram´´: A Tool to Synthesize Immune Monitoring;245
13.6;6 Future Directions;245
13.7;References;248
14;Immunobiology of Cancer Therapies Targeting CD137 and B7-H1/PD-1 Cosignal Pathways;257
14.1;1 Introduction;258
14.2;2 The Costimulatory CD137 Signaling Pathway;260
14.2.1;2.1 The Expression of CD137L and CD137;260
14.2.2;2.2 Role of CD137 Cosignaling in Effector/Memory T Cells;261
14.3;3 Strategies to Augment Tumor Immunity by Stimulating CD137;262
14.3.1;3.1 Tumor Therapy with Agonist Anti-CD137 Antibody;262
14.3.2;3.2 Whole Cell Vaccines with Capacity to Stimulate CD137;264
14.3.3;3.3 Adoptive Transfer of T Cells with CD137 Costimulation;265
14.4;4 The Coinhibitory B7-H1/PD-1 Signaling Pathway;266
14.4.1;4.1 Expression of B7-H1, B7-DC and PD-1;266
14.4.2;4.2 Complex Interactions Among B7-H1, B7-DC, B7-1, PD-1, and Possible Additional Binding Partners;267
14.4.3;4.3 B7-H1/PD-1 Interaction in the Suppression of Immune Responses;268
14.5;5 Manipulation of B7-H1/PD-1 Pathway in Tumor Immunotherapy;269
14.5.1;5.1 B7-H1/PD-1 Pathway in the Evasion of Tumor Immunity;269
14.5.2;5.2 Blocking B7-H1/PD-1 Pathway in Cancer Therapy;271
14.6;References;272
15;LAG-3 in Cancer Immunotherapy;280
15.1;1 Structural Aspects of LAG-3;281
15.1.1;1.1 Basic Structure;281
15.1.2;1.2 LAG-3 Expression;281
15.1.3;1.3 Binding of Class II MHC;282
15.1.4;1.4 Localization of LAG-3 in T Cells;283
15.2;2 LAG-3 Function;283
15.2.1;2.1 Role in CD4 T Cell Function and Expansion;283
15.2.2;2.2 Role of LAG-3 on Regulatory T Cells ;284
15.2.3;2.3 Role of LAG-3 on CD8 T Cells;284
15.2.4;2.4 LAG-3 Mechanism of Action;285
15.3;3 LAG-3 in Cancer Immunotherapy;286
15.3.1;3.1 Preclinical Studies;286
15.3.2;3.2 Clinical Studies;286
15.4;4 Conclusions;287
15.5;References;288
16;Immunologically Active Biomaterials for Cancer Therapy;290
16.1;1 The Challenge of Cancer Immunotherapy;291
16.2;2 Sources and Inspiration for Biomaterials;293
16.2.1;2.1 Raw Materials;293
16.2.2;2.2 Controlled Delivery and Cell Targeting;294
16.2.3;2.3 Synthetic ECMs;295
16.3;3 Antigen Delivery and DC Targeting;296
16.4;4 Adjuvant Materials;299
16.5;5 Three-Dimensional Niches That Regulate Immune Responses In Situ;302
16.6;6 Conclusions and Future Prospects;303
16.7;References;304
17;Erratum: Identification of Human Idiotype-Specific T Cells in Lymphoma and Myeloma;309
18;Index;310