Immune aging and outcomes in adult survivors of childhood cancer

About This Grant

Summary: Childhood cancer survivors carry a high burden of morbidity resulting in a significant reduction in their lifespan. The chronic health conditions including congestive heart failure and coronary artery disease and frailty develop at an earlier age than would be expected in the general population and are thought to be indicators of accelerated aging in adult survivors of childhood cancer. It is important to note that while therapeutic exposures lead to initial tissue damage, modifiable risk factors are now recognized as a major contributor to the development of cardiovascular disease and frailty in childhood cancer survivors, providing a likely intervention to reduce long term morbidity in these individuals. The immune system undergoes several changes with physiologic aging in humans and has been implicated in the pathogenesis of heart disease. Strategies to modulate underlying inflammation are under active evaluation in the setting of heart disease. Our preliminary studies have combined several high-dimensional approaches to identify distinct alterations/dysfunction in immune cells and show that survivors of childhood B-lymphoblastic leukemia exhibit phenotypes consistent with advanced immune aging. Immune health in adult survivors of childhood hematologic malignancies remains unstudied and the magnitude of immune aging in long-term survivors compared with healthy comparison groups is unknown. Finally, it is not clear whether survivors with chronic health conditions are more likely to exhibit immune aging phenotypes when compared with those without such conditions. This application brings together investigators with expertise in immunology and survivorship to test the hypothesis that long-term survivors of childhood hematologic malignancies will exhibit distinct aging-associated immune phenotypes, and that these immune phenotypes will be associated with key chronic health conditions. It will leverage our access to well- annotated biospecimens linked to distinct health outcomes from the Childhood Cancer Survivor Study (CCSS), St Jude life as well as matched healthy controls (Emory University). Access to these resources and tools developed by our group will allow us to 1) compare aging-associated immune phenotypes in adult survivors of childhood hematologic malignancies vs. matched healthy controls and identify demographic, clinical, and therapeutic factors associated with aging-associated immune phenotypes. 2) characterize immune signatures in adult survivors of childhood hematologic malignancies with and without heart disease and physiologic frailty. Our application will not only identify distinct subpopulations of hematologic malignancy survivors at high-risk for immune aging, but also set the stage for future intervention studies to improve immune function in these cohorts and mitigate the risk of adverse outcomes.