Socioeconomic and adversity-associated immunobiologic influences on pediatric hematopoietic cell transplant outcomes - ABSTRACT Patients with high-risk hematological malignancies may be cured using allogeneic hematopoietic cell transplantation (HCT); however, HCT carries a significant risk for mortality. Social adversity accounts for increased risk for morbidity and mortality following HCT in both adults and children. Our group has identified that in adult recipients, not only is this risk disproportionately worse among HCT recipients of low socioeconomic status (SES), but it is worse among recipients receiving hematopoietic cells from donors of low SES. Further, we have demonstrated that up-regulation of a stress- and SES-related transcriptome profile – termed the “conserved transcriptional response to adversity” (CTRA) – within adult HCT donors and recipients may be a biological contributor to cancer outcomes disparities. However, it is unknown whether low donor SES and donor/recipient stress-related immunobiological factors, such as CTRA expression and biological aging (both linked to poorer outcomes in cancer and HCT patients), pose a prognostic risk to pediatric HCT recipients. Despite our novel findings in adults, they cannot be extrapolated to pediatric patients because pediatric patients are diagnosed with cancer that is biologically unique from adults and they experience stress and illness differently than adults. The goal of this research is to extend our understanding of whether the immunobiologic mechanisms underlying the comorbidity of social health disparities in adult cancer and HCT extend to the biologically and psychosocially unique pediatric cancer population, providing a critical link for designing interventions to reduce cancer disparities. The primary aims of this proposal are to: 1) quantify how donor and recipient SES are associated with pediatric HCT outcomes; 2) evaluate how HCT donor and pediatric recipient SES affects biologic indicators of stress (CTRA, biological aging); and 3) determine the relationship between donor and recipient stress biology factors and clinical outcomes in pediatric HCT patients. Our overarching hypothesis is that SES- related immunobiologic risk factors will be associated with pediatric recipient and donor SES, and that both will be associated with inferior pediatric HCT outcomes, including disease-free survival, transplant-related mortality, relapse, graft-versus-host disease, and overall survival. The research plan employs molecular biology to investigate immunobiologic factors underlying health disparities by collaborating with the federally funded Center for International Blood and Marrow Transplant Research. We will leverage the expertise of a multidisciplinary investigator team by using clinical (N=1716 donor/recipient pairs) and biological (N=946 each for donors and recipients) data for donors and recipients in the pediatric HCT population. By identifying SES-related immunobiological risk factors for adverse pediatric HCT outcomes, we have the opportunity to optimize HCT outcomes and address potential biological mechanisms of cancer disparities. The proposed work will define the gene regulatory understanding of SES disparities in pediatric cancer treatment outcomes, providing critical data to design interventions for improving outcomes across the age continuum.
