Emerging Concepts Targeting Immune Checkpoints in Cancer and Autoimmunity 1st Edition by Akihiko Yoshimura ISBN 3319689290 9783319689296

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ISBN 10: 3319689290 
ISBN 13: 9783319689296
Author: Akihiko Yoshimura

This volume reviews the current state of research on immune checkpoints and offers novel concepts. It discusses the two most important immune checkpoints: T lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death-1 (PD-1). It shows that antagonistic antibodies against these two molecules are highly effective in the treatment of various cancers and that PD-1 and CTLA-4 have been linked to the suppression of T-cell receptor signaling and co-stimulatory molecules. Further, the volume examines other agents, a number of cells, receptors and signaling molecules, that are also involved in the regulation of T-cell activation and extends the concept of immune checkpoints to “molecules and cells that negatively regulate T-cell activation”. Playing essential roles in immune homeostasis, they could offer new targets for cancer immunotherapy, and for the therapy of autoimmune diseases. Written by internationally respected scientists, this book will appeal to basic scientists, clinicians, drug development researchers, and advanced students alike.

Emerging Concepts Targeting Immune Checkpoints in Cancer and Autoimmunity 1st Table of contents:

1 Introduction
2 Development and Maintenance of Tregs
2.1 TCR, CD28, and IL-2
2.2 PI3K-Akt-mTOR
2.3 Epigenetics
3 Functional Classification of Tregs
4 Suppressive Mechanism of Tregs
5 Tregs and Autoimmune Diseases
5.1 Treg Cell Therapy for Autoimmune Diseases
5.2 Non-Cell-Based Therapies
6 Tregs and Malignant Tumors
6.1 Trafficking and Characteristics of Tregs in Cancer
6.2 Strategies for Treg-Targeted Therapy
6.3 Involvement of Tregs in Immune Checkpoint Inhibitors
7 Conclusion
References
59 Overview of LAG-3-Expressing, IL-10-Producing Regulatory T Cells
Abstract
1 Introduction
2 Features of IL-10-Producing Treg Cells
3 Molecular Properties of LAG-3
4 Identification of LAG-3 as a Marker for IL-10-Producing Treg Cells
5 CD4+CD25−LAG3+ Treg Cells Control Humoral Immunity Via TGF-β3
6 Egr2 and Egr3 Cooperatively Control Systemic Autoimmunity Through TGF-β3 Production by CD4+CD25
7 Identification of CD4+LAG3+CD49b+ Cells
8 Roles of CD4+LAG3+ Cells or CD4+LAG3+ CD49b+ Cells
9 LAG-3- and/or PD-1-Expressing CD4+ T Cells in Malignancy
10 LAG-3 and/or PD-1 Expressing CD4+ T Cells in Infection
11 Conclusions
Acknowledgements
References
60 Regulatory Dendritic Cells
Abstract
1 Introduction
2 Overview of DC Biology
3 DC Subsets and Functions
3.1 Mouse cDC Subsets and Functions
3.2 Mouse pDC Subsets and Functions
3.3 Mouse Inflammatory DC Subsets and Functions
3.4 Human cDC Subsets and Functions
3.5 Human pDC Subsets and Functions
3.6 Human Inflammatory DC Subsets and Functions
4 Tolerogenic DCs and Functions
4.1 Tolerogenic DCs and Functions
4.2 Clinical Application of Human Tolerogenic DCs
5 Regulatory DCs and Functions
5.1 Human Regulatory DCs and Functions
5.2 Murine Regulatory DCs and Functions
6 Conclusions
References
Extracellular Immune Checkpoint Molecules
Part II Extracellular Immune CheckpointMolecules
67 Role of PD-1 in Immunity and Diseases
Abstract
1 Introduction
2 History of PD-1 and Its Ligands
2.1 Discovery
2.2 Structure
3 Molecular Functions
4 Expression and Biological Roles
4.1 Expression Profile of PD-1 and PD-Ls
4.2 Role in Autoimmunity
4.3 Role in Viral Immunology
4.4 Role in Tumor Immunology
5 Issues and Future Directions in PD-1 Blockade Cancer Immunotherapy
References
61 CTLA-4, an Essential Immune-Checkpoint for T-Cell Activation
Abstract
1 Introduction: CD28 and CTLA-4 as Checkpoints
2 Structure of CTLA-4
2.1 Discovery and Primary Structure of CTLA-4
2.2 Alternatively Spliced Isoforms of CTLA-4
3 Function of CTLA-4
3.1 Cell-Intrinsic T-cell Inhibition by CTLA-4
3.2 Cell-Extrinsic T-Cell Inhibition by CTLA-4
4 Mechanisms of CTLA-4-Mediated Immune Regulation
4.1 The Biochemical Partners of CTLA-4
4.1.1 SHP-2
4.1.2 PP2A
4.1.3 PKC-η(Eta)
4.1.4 Clathrin Adaptor Complex
4.1.5 Tyrosine Kinases
4.2 Induction and Dynamic Localization of CTLA-4 to the Immunological Synapse
4.2.1 Induction of CTLA-4 on T Cells
4.2.2 CTLA-4 Storage
4.2.3 CTLA-4 Localization and Inhibition at the Immunological Synapse
4.2.4 Internalization and Trans-Endocytosis
4.3 Structure and Functional Relationship
5 Biological Roles of CTLA-4
5.1 CTLA-4 Genetics in Autoimmunity: Mice to Humans
5.2 CTLA-4 in Infection
5.3 CTLA-4 in Cancer
Acknowledgements
References
62 Tim-3, Lag-3, and TIGIT
Abstract
1 Introduction
2 Tim-3
2.1 Signaling
2.2 Tim-3 in Innate Cells
2.3 Role of Tim-3 in Effector Cells
2.4 Role of Tim-3 in Regulatory Cells
3 Lag-3
3.1 Signaling
3.2 Role of Lag-3 in Effector Cells
3.3 Role of Lag-3 in Regulatory Cells
4 TIGIT
4.1 Signaling and Direct Inhibition
4.1.1 TIGIT in Effector Cells
4.1.2 TIGIT in Regulatory Cells
4.2 Indirect Inhibition
5 Role in Diseases and Therapy
5.1 T Cell Exhaustion
5.2 Cancer and Checkpoint Inhibitors
5.3 Autoimmunity
6 Conclusion
Acknowledgements
References
Intracelluar Immune Checkpoint Molecules
63 SOCS1: Regulator of T Cells in Autoimmunity and Cancer
Abstract
1 Introduction
2 SOCS1-Dependent Regulation of Cytokine Signaling
3 Regulation of T Cell Activation and Homeostasis by SOCS1
4 Role of SOCS1 in T Cell Development
5 Regulation of Treg Plasticity and Function by SOCS1
6 Influence of SOCS1 on Antigen Presenting Cell Functions
7 SOCS1 as an Immune Checkpoint Molecule
8 Targeting SOCS1 in Autoimmunity and Cancer
Acknowledgments
References
68 Mining the Complex Family of Protein Tyrosine Phosphatases for Checkpoint Regulators in Immunity
Abstract
1 Protein Tyrosine Phosphatases and the Mammalian Immune System
1.1 The Protein Tyrosine Phosphatase Gene Family
1.2 Protein Tyrosine Phosphatases in Immunity
1.3 Regulation of Protein Tyrosine Phosphatases
2 The Concept of Immune Checkpoints and PTPs
3 Protein Tyrosine Phosphatases as Immune Checkpoint Regulators in Monocytes and Macrophages
3.1 Background
3.2 PTP Expression in Macrophages
3.3 PTP Regulation of JAK/STAT Signaling and the Pro-inflammatory Response
3.4 Regulation of Macrophage Activation and Polarization by PTPs
4 PTPs as Negative Immune Checkpoint Regulators of Dendritic Cell Function
4.1 Background
4.2 PTP Expression in DCs
4.3 PTP Regulation of TLR and Cytokine Receptor Signals in DCs
4.4 PTPs as Regulators of DC Maturation and T Cell Differentiation
4.5 PTP Regulation of Cell Migration and Vesicle Transport
5 PTPs as Components of Inhibitory Signaling in T Cells
5.1 PTPs as Transducers of Checkpoint Signals in T Cells
5.2 PTPs in CTLA-4 Signaling
5.3 PTPs in PD-1 Signaling
5.4 Other Inhibitory Molecules of the CD28 Family
5.5 Other ITIM-Containing Receptors
5.6 ITSM Signaling
5.7 SAP Family of Adaptors as “Natural” Checkpoint Inhibitors
5.8 JAK/STAT Regulation by PTP1B and TC-PTP
6 Conclusion
Acknowledgements
References
64 Immune Regulation by Ubiquitin Tagging as Checkpoint Code
Abstract
1 Introduction
2 Cbl-b as a Key Regulator in T Cells
2.1 Cbl-b in T Cell Receptor Signaling
2.2 Cbl-b in T Cell Anergy
2.3 Cbl-b in T Cell Subsets
2.4 Cbl-b in Anti-tumor Immunity
3 The E3 Ligase Itch in T Cell Regulation
3.1 Itch in Th2 Cells
3.2 Itch in Tfh Differentiation
3.3 Itch in Th17 Differentiation
3.4 Itch in T Cell Anergy
4 Control of Treg Cells by Ubiquitination
4.1 Treg Cells in Immune Tolerance
4.2 VHL
4.3 SHARPIN
4.4 Itch
4.5 Cbl-b
4.6 GRAIL
4.7 TRAF6
5 Deubiquitinase A20 in Immune Regulation
5.1 A20 Functions in Lymphoid Cells
5.2 A20 Functions in Non-lymphoid Cells
5.3 The Role of A20 in TNF-Induced NFκB Activation
5.4 A20 Functions in Other Signaling Pathways
5.5 Regulation of A20
6 CYLD
6.1 CYLD in NFκB Signaling
6.2 CYLD in T Cell Development
6.3 CYLD in Lymphocyte Function
6.4 CYLD Function in Treg Cells
7 Concluding Remarks
Acknowledgements
References
65 MicroRNA in Immune Regulation
Abstract
1 Introduction
2 miRNAs in the Immune System
3 miRNAs as Negative Regulators of Immune Responses
3.1 miRNA in Adaptive Immunity
3.2 miRNA in Innate Immunity
4 miRNAs in Human Immunological Diseases
4.1 miRNA in Autoimmunity and Hypersensitivity Diseases
4.2 miRNA in Blood Cancer
5 Other Non-coding RNAs
6 Concluding Remarks

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