Mechanisms of efficacy and toxicity of immune checkpoint inhibitors in human cancer patients Open Access

Abstract

Immune checkpoint inhibitors (ICIs) have revolutionized the landscape of cancer treatment, leading to impressive and durable results in patients with a wide range of tumor types. However, significant clinical challenges remain surrounding patient response rates and autoimmune toxicities. Herein, we investigate the underlying mechanisms of efficacy and toxicity in human cancer. We assessed changes in circulating immune cells among patients who received either anti-PD-1 or anti-PD-L1, finding distinct, nonoverlapping genomic signatures of each. In particular, anti-PD-L1 is characterized by changes in the myeloid compartment, with increased signatures associated with inflammation. Importantly, we find that PD-L1 blockade acts directly on DCs, resulting in enhanced maturation and expansion of antigen-specific T cells, suggesting a key role of anti-PD-L1 within the afferent arm of the cancer immunity cycle. Furthermore, we establish a novel role for T:B interactions in the development of immune-related adverse events (irAEs) following combination anti-CTLA-4 and anti-PD-1 (CCB) therapy. We show CCB leads to the enrichment of TPH-like cells, which support B cell activation and differentiation through IFNg and IL-21 signaling. Importantly, we highlight key cellular and molecular differences associated with the development of severe irAEs. First, we illustrate alterations in circulating CD11c+Tbet+CD21lo B cells in patients with severe irAEs following CCB, suggesting a pathogenic role. We also report that the expansion of Tregs suppresses T:B interactions, protecting patients from irAEs. Thus, the work presented here provides new insights into the cellular and molecular mechanisms of ICI efficacy and toxicity, furthering the understanding of ICIs and ultimately improving patient outcomes.

Table of Contents

Table of Contents

 

Abstract……………………………………………………………………………………………ii

Acknowledgements…………………………………………………………………………...…..iv

Table of Contents………………………………………………………………………...……….vi

List of Figures…………………………………………………………………………………..viii

List of Tables………………………………………………………………………………………x

List of Abbreviations……………………………………………………………………………...xi

Chapter 1: Introduction………………………………………………………………………….1

           1.1 Introduction to cancer and the immune system……………..…..…………………...…1

1.2 Targeting checkpoint molecules using monoclonal antibodies….……………………..5

           1.3 Underlying mechanisms of ICI efficacy.....…….………………..…………………...12

           1.4 Immune related adverse events induced by ICI……………………………...…….…14

           1.5 Summary, scope, and goals for this project…………………………………………..18

Chapter 2: Differential effects of PD-L1 versus PD-1 blockade on myeloid inflammation in human cancer………………………………………………………………………….………..19

2.1 Abstract…..…..…………………………………..…………………………………..21

2.2 Key Findings…..…………………………………..………..………………………..21

2.3 Introduction…..…………………………………..………………………………..…22

           2.4 Results………………………………………………………………………………..25

           2.5 Discussion……………………………………………………………………………44

           2.6 Materials & Methods…………………………………………………………………50

           2.7 Acknowledgements…………………………………………………………………..60

Chapter 3: Tregs protect against combination checkpoint blockade toxicity induced by TPH and B cell interactions…………………..……………...………………………………...61

           3.1 Key Findings..………………………………………………………………………..62

           3.2 Introduction..…..……………………………………………………………………..62

           3.3 Results………………………………………………………………………………..65

           3.4 Discussion……………………………………………………………………………72

           3.5 Materials & Methods…………………………………………………………………72

           3.6 Acknowledgements…………………………………………………………………..77

Chapter 4: General Discussion and Closing Remarks………………………………………..78

           4.1 Introduction…………………………………………………………………………..78

           4.2 Effects of PD-L1 blockade on dendritic cell function………………………………..79

           4.3 Importance of T:B crosstalk in CCB-induced irAEs……………………..…………..84

           4.4 Future Studies and Closing Remarks…………………………………………………91

Chapter 5: References…………………………………………………………………………..98

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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	Health Sciences, Immunology Biology, General Health Sciences, Oncology
Keyword	Immunotherapy Checkpoint Inhibitors Cancer Immunology
Committee Chair / Thesis Advisor	Kavita Dhodapkar, Emory University
Committee Members	Ignacio Sanz, Emory University Haydn Kissick, Emory University Greg Lesinski, Emory University Madhav Dhodapkar, Emory University

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