Understanding immune-aging in myeloma and its precursor states Público

Abstract

Myeloma and its precursor monoclonal gammopathy (MGUS) are more common in individuals with Black ancestry and associated with immune dysfunction. Mechanisms linking immune dysfunction to racial ancestry or malignant transformation remain unclear. Here we show that blood/marrow T cells from myeloma patients exhibit enhanced capacity for inflammatory cytokine production and proliferation including in cells with phenotypes previously linked to T-cell exhaustion. In chronologically age-matched cohorts, myeloma patients have greater aging- associated immune changes compared to MGUS patients. MGUS patients with Black ancestry exhibit greater immune- aging compared to White counterparts. Myeloma T cells exhibit altered inflammatory phospho-proteomic signaling and was associated with distinct transcriptional profiles of immune and tumor cells in the bone marrow. Immune-aging correlated with responses to SARS CoV-2 vaccination, providing a correlation between immune aging and immune function in vivo. Maladaptive immune-aging may underlie racial predisposition and impact malignant transformation and immune responses in MM.

Table of Contents

Abstract.........................................................................................................ii

Acknowledgements............................................................................................iv

Table of Contents...............................................................................................v

List of Figures................................................................................................vii

List of Tables................................................................................................. viii

List of Abbreviations..........................................................................................ix 

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

1.1 Myeloma and evolution from precursor states................................................1

1.2 Tumor microenvironment........................................................................5

1.3 Role of the immune system in MGUS and myeloma.........................................6

1.3.1 Introduction to cancer immune surveillance........................................6

1.3.2 Immune surveillance and recognition in MGUS and MM........................7

1.3.3 T cells in Myeloma....................................................................9

1.4 Aging and Cancer...............................................................................11

1.4.1 Hallmarks of Aging..................................................................11

1.4.2 Links between Aging and Cancer..................................................12

1.4.3 Effect of aging on T cells............................................................13

1.4.4 Inflammatory signatures seen in aging and cancer................................14

1.4.5 Immune aging and vaccine response...............................................16

1.4.6 Age calculators.......................................................................16

1.5 The epidemiology of myeloma................................................................20

1.5.1 Myeloma and aging..................................................................20

1.5.2 Myeloma and race...................................................................20

1.6 Summary, scope, and goals for this project...................................................22 

Chapter 2: T cells from Myeloma patients lack global exhaustion....................................23 

2.1 Key Findings................................................................................................................24

2.2 Introduction..................................................................................................................24

2.3 Results..........................................................................................................................25

2.4 Discussion....................................................................................................................33

2.5 Materials & Methods....................................................................................................33

2.6 Acknowledgements......................................................................................................37

Chapter 3: Immune cells from Myeloma patients are immune aged........................................38

3.1 Key Findings................................................................................................................39

3.2 Introduction..................................................................................................................39

3.3 Results..........................................................................................................................40

3.4 Discussion....................................................................................................................58

3.5 Materials & Methods....................................................................................................59

3.6 Acknowledgements......................................................................................................68

Chapter 4: General Discussion and Closing Remarks...............................................69

4.1 Introduction......................................................................................69

4.2 Investigation of immune-aging in myeloma................................................70

4.3 Racial differences in myeloma and its precursor states....................................71

4.4 Future directions.................................................................................71

Chapter 5: References......................................................................................77

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	Health Sciences, Aging Health Sciences, Immunology
Palabra Clave	Myeloma Immune-aging
Committee Chair / Thesis Advisor	Kavita Dhodapkar, Emory University
Committee Members	Gregory Lesinski, Emory University Haydn Kissick, Emory University Madhav Dhodapkar, Emory University Lawrence Boise, Emory University

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