Delineating How Aging- and Obesity-Associated Chronic Inflammation Impacts B-cell Acute Lymphoblastic Leukemia Progression Open Access
Hamilton,Jamie (Fall 2022)
Abstract
Acute lymphoblastic leukemia (ALL) is a blood cancer derived from an overabundance of immature lymphocytes. Leukemia is classified based on the lymphocyte that transforms, such as B-cells or T-cells. B-cell malignancies are the most common cancer in children, with B-cell acute lymphoblastic leukemia (B-ALL) accounting for 80% of all ALL. Currently, survival outcomes for patients with B-ALL exceed 80%; however, in patients with relapsed or refractory disease, survival outcomes are significantly lower. Furthermore, comorbidities, like advanced age or obesity, are reported to decrease survival outcomes. Both conditions are associated with a loss of immunological homeostasis with the hallmark induction of chronic inflammation. In this dissertation, I present my results demonstrating that targeting the inflammatory microenvironment improves the efficacy of chemotherapies and immunotherapies in aged and obese settings of B-ALL.
In the context of obesity, I discovered that the cytokine interleukin-9 (IL-9), which has mainly been studied in the context of allergic reactions, is secreted by murine and human adipocytes. Furthermore, as reported in other hematological malignancies, I discovered that IL-9 drives B-ALL progression by decreasing the pro-apoptotic mediator BIM. Notably, I also discovered that circulating IL-9 levels positively correlates with BMI in pediatric patients with B-ALL. In addition to IL-9 impacting B-ALL progression, in the context of aging, I found that aging-associated reductions in interleukin-37 (IL-37) levels were associated with reduced T-cell mediated immunosurveillance of B-ALL cells. Furthermore, I found that elevating IL-37 levels in aged backgrounds, improved T-cell. Mechanistically, this effect was achieved by decreasing elevated homeostatic NF-κB levels in aged T-cells. In xenograft models of B-ALL, in which aged mice were treated with aged chimeric antigen receptor (CAR) T-cells generated from a 67-year-old donor; aged mice with the longest survival outcomes were those that received the combination of recombinant IL-37 and CAR T-cell therapy.
Collectively, my studies demonstrate that aging and obesity impacts B-ALL progression, in part, by altering immunological homeostasis. Furthermore, I present data demonstrating that targeting or resupplying pro-inflammatory or anti-inflammatory cytokines, respectively, has therapeutic potential and should be considered for further exploration as novel therapeutic option for hematological malignancies in patients with underlying comorbidities.
Table of Contents
Chapter 1: Introduction
1.1 Overview
a. Aging
b. Obesity
c. Aging, Obesity & Cancer Progression
1.2 B-ALL Overview
a. Patient Demographics
b. Disease Mechanism
c. Chemotherapy Treatments
1.3 Immunotherapy in B-ALL
a. Blinatumomab
b. CAR-T cell therapy
c. Neutralizing Antibodies
d. Checkpoint Inhibitors
1.4 Challenges to B-cell Immunotherapy
a. Immunosuppressive tumor microenvironment
b. T-cell exhaustion & Summary of Introduction
Chapter 2: Utilizing Interleukin-37 treatment to boost anti-leukemia mediated immunity in aged background
2.1 Abstract
2.2 Introduction
2.3 Materials & Methods
2.4 Results
2.5 Discussion
2.6 Figures, Supplemental Figures & Tables
Chapter 3: Adipocyte-secreted Interleukin-9 Promotes B-cell Acute Lymphoblastic Leukemia Progression
3.1 Abstract
3.2 Introduction
3.3 Materials & Methods
3.4 Results
3.5 Discussion
3.6 Figures, Supplemental Figures & Tables
Chapter 4: Discussion
4.1 Summary and implications of results
4.2 Limitations and Future Directions
About this Dissertation
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Delineating How Aging- and Obesity-Associated Chronic Inflammation Impacts B-cell Acute Lymphoblastic Leukemia Progression () | 2022-10-24 13:10:22 -0400 |
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Supplemental Files
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