An intratumoral immune niche sustains the anti-tumor immune response and supports the response to immunotherapy 公开

Abstract

Tumor infiltrating lymphocytes have been associated with a survival benefit in many tumor types, as well as with the response to immunotherapy. However, it is not clear why some tumors are infiltrated by many T cells, but others have relatively few. Herein, we investigate the mechanisms required for maintaining a strong anti-tumor T cell response in human cancers. We demonstrate that the T cell response is both functionally compartmentalized and physically organized, where a stem-like T cell both self-renews, as well as differentiates into more terminally differentiated, effector-like daughter cells. We show that the presence of these two cell types, and the critical differentiation of the stem-like cells, is integral to a robust anti-tumor immune response. Furthermore, we show that these stem-like T cells reside in antigen presenting cell-dense immune niches within the tumor, and that tumors with an absence or loss of these niches fail to maintain a strong anti-tumor T cell response. Importantly, we illustrate that this biology is translatable across multiple tumor types, reporting these findings in renal cell carcinoma, prostate cancer, and brain metastases from patients with diverse tumor types. Importantly, in renal cell carcinomas and brain metastases, we find the substantial presence of these immune niches leads to significantly improved clinical outcomes. As such, the data presented here provides a strong foundation for understanding the mechanisms of the T cell response to human cancer and provides a springboard for future investigation and continued clinical translation for the benefit of patients of many different tumor types.

Table of Contents

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

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

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

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

List of Tables……………………………………………………………………………………...xi

List of Abbreviations……………………………………………………………………………..xii

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

            1.1 Introduction……………………………………………………………………………1

            1.2 The importance of the immune system in the control and prevention of cancer………1

            1.3 T cell dynamics in the environment of chronic antigen exposure……………………..5

            1.4 Summary, scope, and goals for this project……………………………………………8

Chapter 2: An intra-tumoral niche maintains and differentiates stem-like CD8 T-cells…..10

            2.1 Author’s Contribution and Acknowledgement of Reproduction…………………….10

            2.2 Abstract………………………………………………………………………………11

            2.3 Introduction…………………………………….…………………………………….12

            2.4 Results………………………………………………………………………………..13

            2.5 Discussion……………………………………………………………………………42

            2.6 Materials & Methods…………………………………………………………………47

            2.7 Acknowledgements…………………………………………………………………..56

            2.8 Tables………………………………………………………………………………...58

Chapter 3: Stem-like CD8 T cells are present in intra-tumoral immune niches in diverse tumor types……………………………………………………………………………………...60

            3.1 Author’s Contribution and Acknowledgement of Reproduction…………………….60

            3.2 Introduction…………………………………………………………………………..61

            3.3 Results………………………………………………………………………………..63

            3.4 Discussion……………….……………….……………….……………….….……...90

            3.5 Materials & Methods….……….……….……….……….……….……….……….....94

            3.6 Acknowledgements……………….……………….……………….………………...98

            3.7 Tables….……….……….……….……….……….……….……….……….………..99

Chapter 4: Clinical outcomes following immunotherapy in renal cell carcinoma patients is associated with a pre-existing immune response in tumor tissue….……….……….……….101

            4.1 Introduction….……….……….……….……….……….……….……….…………101

4.2 Results….……….……….……….……….……….……….……….……….……...103

            4.3 Discussion….……….……….……….……….……….……….……….……….….114

            4.4 Materials & Methods….……….……….……….……….……….……….………...118

            4.5 Acknowledgements….……….……….……….……….……….……….……….…120

            4.6 Tables….……….……….……….……….……….……….……….……….………121

Chapter 5: General Discussion and Closing Remarks….……….……….……….……….…124

5.1 Introduction…………………………………………………………………………124

            5.2 TCF1+ stem-like T cells in human tumors………………………………….………124

            5.3 Stem-like T cells reside in an intratumoral immune niche…..………………………126

            5.4 Immune niches and the response to immunotherapy….……………………………130

            5.5 Future studies and concluding remarks………………..……………………………131

Chapter 6: References….……….……….……….……….……….……….……….…………141

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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
关键词	immunotherapy immunology cancer immunology T cell cancer biology immune niche immune organization
Committee Chair / Thesis Advisor	Kissick, Haydn, Emory University
Committee Members	Ford, Mandy, Emory University Lesinski, Greg, Emory University Mainou, Bernardo, Emory University Master, Viraj, Emory University

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