T Cell Dysfunction and Checkpoint Blockade in Sepsis Público

Abstract

Sepsis is the leading cause of death in the United States, with mortality rates of septic individuals at ~20%. Immune dysregulation, including T cell exhaustion, has been documented during sepsis. However, the mechanisms underlying sepsis-induced T cell dysfunction remain poorly understood. During my dissertation work, we observed that a co-signaling molecule, 2B4 (CD244, SLAM4) is up-regulated on exhausted CD4⁺T cells in septic patients. To determine the role of 2B4 on CD4⁺T cell dysfunction during sepsis, cecal ligation and puncture (CLP) was performed on animals as a murine sepsis model. We identified an important inhibitory role of 2B4 on CD4⁺T cell-mediated T cell dysfunction and CLP mortality in animals. Of note, therapeutic blockade of 2B4 improved mortality in septic animals. 

Cancer represents one of the most common comorbidities in sepsis with the in-hospital mortality at 40%. Approximately 100,000 cancer patients die due to sepsis annually. Checkpoint blockade is a promising therapy for cancer, and PD-1 blockade has recently also shown encouraging results in experimental models of sepsis. Here we aimed to determine the efficacy of PD-1 blockade in a pre-existing cancer sepsis model. We demonstrate that PD-1 blockade failed to improve mortality in cancer septic animals, while 2B4 blockade improved survival in cancer septic animals by modulating the balance of co-signaling receptors on T cells. Moreover, to investigate the mechanisms underlying increased mortality in cancer sepsis, we developed a novel model that allows us to track tumor-specific T cells during cancer sepsis.  We showed that tumor-specific T cells in the tumor tissue were less impacted by sepsis-induced dysfunction. In addition, we found that tumor-specific T cells partially contributed to sepsis mortality in cancer septic animals by affecting endogenous CD8⁺T cells apoptosis. These findings illustrate a novel role of 2B4 in mediating T cell dysfunction during sepsis and also define the interplay between tumor-specific T cells and sepsis pathophysiology. 

Table of Contents

Chapter 1.      Introduction

1.1       Introduction of sepsis

1.1.1        The evolution of the definition of sepsis

1.1.2        Animal models for sepsis

1.1.3        Sepsis and comorbidity with malignancy

1.2       Immune dysregulation in sepsis

1.2.1        The hyper-inflammatory response in sepsis

1.2.2        The immunosuppressive response in sepsis

1.2.3        Targeting immunosuppression as the potential therapy for sepsis

1.3       Co-stimulatory and co-inhibitory receptors regulate T cell responses

1.3.1        Co-stimulatory receptor: CD28

1.3.2        Co-inhibitory receptor: CTLA-4

1.3.3        Co-inhibitory receptor: PD-1

1.3.4        Dual function receptor: 2B4

1.4       Figure and Tables

1.5       References

Chapter 2.      2B4-mediated co-inhibition of CD4⁺T cells underlies mortality in experimental sepsis

2.1       Abstract

2.2       Introduction

2.3       Results

2.4       Discussion

2.5       Acknowledgments

2.6       Materials and Methods

2.7       Figures and Figure Legends

2.8       References

Chapter 3.      2B4 but not PD-1 blockade improves mortality in septic animals with pre-existing malignancy

3.1       Abstract

3.2       Introduction

3.3       Results

3.4       Discussion

3.5       Materials and Methods

3.6       Figures and Figure Legends

3.7       References

Chapter 4.      Tumor specific T cells exacerbate mortality and immune dysregulation in cancer sepsis..

4.1       Abstract

4.2       Introduction

4.3       Results

4.4       Discussion

4.5       Materials and Methods

4.6       Figures and Figure Legends

4.7       References

Chapter 5.      Discussion

5.1       Discussion

5.2       Figures and Figure Legends

5.3       References

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Biology, General Biology, Cell
Palavra-chave	Checkpoint Blockade Sepsis Immunology
Committee Chair / Thesis Advisor	Mandy L. Ford, Emory University
Committee Members	Timothy G. Buchman, Emory University Brian D. Evavold, Utah University Luisa Cervantes-Barragan, Emory University Craig Coopersmith, Emory University Rabin M. Tirouvanziam, Emory University

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