Delineating How Aging- and Obesity-Associated Chronic Inflammation Impacts B-cell Acute Lymphoblastic Leukemia Progression Open Access

Hamilton,Jamie (Fall 2022)

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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                                                                                              

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