The Yes-Associated Protein (YAP) promotes resistance to anti-GD2 immunotherapy in neuroblastoma through downregulation of ST8SIA1 Público

Abstract

Pediatric patients with high-risk neuroblastoma often relapse with chemotherapy-resistant, incurable disease. Relapsed neuroblastomas harbor chemo-resistant mesenchymal tumor cells and increased expression/activity of the transcriptional co-regulator, the Yes-Associated Protein (YAP). Patients with relapsed neuroblastoma are often treated with immunotherapy such as the anti-GD2 antibody, dinutuximab, in combination with chemotherapy. Since YAP mediates both chemotherapy and MEK inhibitor resistance in relapsed RAS mutated neuroblastoma, we posited that YAP might also be involved in anti-GD2 antibody resistance. We now show that YAP inhibition significantly enhances sensitivity of mesenchymal neuroblastomas to dinutuximab and gamma delta (γδ) T cells both in vitro and in vivo. Mechanistically, YAP inhibition induces increased GD2 cell surface expression through upregulation of ST8SIA1, the gene encoding GD3 synthase, the rate-limiting enzyme in GD2 biosynthesis. The mechanism of ST8SIA1 suppression by YAP is independent of PRRX1 expression, a mesenchymal master transcription factor, suggesting YAP may be the downstream effector of mesenchymal GD2 resistance. These results therefore identify YAP as a potential therapeutic target to augment GD2 immunotherapy responses in patients with neuroblastoma.  

Table of Contents

Chapter I: Introduction

1.1 Definition, diagnosis, risk stratification, and treatment of neuroblastoma

1.1.1 Clinical presentation and diagnosis of neuroblastoma

1.1.2 Risk stratification and classification of neuroblastoma

1.1.3 Treatment of neuroblastoma

1.2 Genetic alterations in neuroblastoma

1.2.1 MYCN amplification

1.2.2 ALK mutations

1.2.3 Telomere maintenance mechanisms and chromosomal segmental alterations

1.2.4 RAS/MAPK pathway activation

1.3 Developmental origins and phenotypic plasticity of neuroblastoma

1.3.1 Developmental origins of neuroblastoma

1.3.2 Phenotypic plasticity of neuroblastoma

1.4 Summary of the content of this dissertation

Chapter II: The role of the Yes-Associated Protein (YAP) and its paralog, transcriptional co-activator with PDZ-binding motif (TAZ) in cancer

2.1 Structure, signaling, and function of YAP and TAZ

2.1.1 Structure of YAP/ TAZ

2.1.2 Regulation of YAP/ TAZ

2.1.3 Mechanisms of transcriptional control by YAP/TAZ

2.2 Cell-autonomous and tumor microenvironmental functions of YAP/TAZ in tumorigenesis.

2.2.1 Tumor cell-autonomous functions of YAP/TAZ in cancer

2.2.2 The tumor microenvironmental role of YAP/TAZ in cancer

2.3 Therapeutic targeting of YAP/TAZ

2.4 The role of YAP/TAZ in neuroblastoma.

Chapter III: γδ T cell biology, GD2 and GD2-targeting immunotherapies

3.1 The biology of γδ T cells

3.1.1 Development, structure and function of γδ T cells

3.1.2 γδ T cells in cancer

3.1.3 γδ T cells as an immunotherapy

3.2 The glycosphingolipid GD2 and its biological significance

3.2.1 Glycobiology and biosynthesis of GD2

3.2.2 GD2 expression in cancers including neuroblastoma

3.3 GD2-targeting immunotherapies

3.3.1 GD2 as a cancer immunotherapeutic target

3.3.2 Optimizing response to anti-GD2 immunotherapy

Chapter IV: The Yes-Associated Protein (YAP) promotes resistance to anti-GD2 immunotherapy in neuroblastoma through downregulation of ST8SIA1.

4.1 Introduction

4.2 Materials and Methods

4.3 Results

4.4 Discussion

4.5 Supplementary figures and tables

Chapter V: Conclusions and Future Directions

5.1 Summary of findings and implications of this study

5.2 Limitations of this work and future directions

5.2.1 Mechanism of YAP-GD2 regulation in neuroblastoma

5.2.2 The role of TAZ in regulation of GD2 in neuroblastoma

5.2.3 Role of YAP inhibition in sensitization to γδ T cell cytotoxicity

5.3 Overall Conclusions

References

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Cancer Biology
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Biology, Cell
Palabra Clave	cancer neuroblastoma immunotherapy
Committee Chair / Thesis Advisor	Kelly Goldsmith, Emory University
Committee Members	Melissa Gilbert-Ross, Emory University Adam Marcus, Emory University Chrystal Paulos, Emory University Steven Sloan, Emory University

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