Patients with high risk or relapsed hematological malignancies may be cured using allogeneic hematopoietic cell transplantation (HCT); however, HCT carries a significant risk of mortality. Our group has identified that this risk is disproportionately worse among recipients of low socioeconomic status (SES). HCT is increasingly used to treat a variety of malignancies and hematologic disorders, yet social adversity continues to account for higher rates of morbidity and mortality from this cancer treatment. We have previously identified a recipient- level SES-related immunobiologic factor implicated in adverse allogeneic HCT patient outcomes - a gene expression pattern termed the ?conserved transcriptional response to adversity? (CTRA). A significant component of the CTRA profile is pro-inflammatory. Reciprocally, several donor-level characteristics are important in predicting allogeneic HCT outcomes. Further, donor cells engraft in the recipient, such that subsequent hematopoiesis is donor-derived. Despite this, it is not known whether donor immunobiologic disparities associated with SES confer additional prognostic risk to HCT recipients. The goal of this research project is to identify SES-related donor-level immunobiologic risk factors for adverse HCT outcomes. The primary aims of this proposal are to: 1) quantify how donor SES alters recipient HCT outcomes; 2) determine the relationship between donor SES and gene expression and the effect of donor gene expression on recipient HCT outcomes; and 3) evaluate the interaction of donor and recipient SES on clinical outcomes and quantify the combined effects of donor and recipient gene expression on clinical outcomes. Our overarching hypothesis is that SES-related pro-inflammatory gene expression patterns in donors will be associated with inferior recipient HCT outcomes, and that this effect will be synergistic with recipient gene expression patterns in influencing recipient outcomes. The research plan employs molecular biology and immunologic techniques to investigate immunobiologic factors underlying health disparities by collaborating with the federally funded Center for International Blood and Marrow Transplant Research (CIBMTR). We will leverage the expertise of a multidisciplinary team of principal investigators, co-investigators, and consultants by using clinical (N=2840) and biological (N=184) HCT donor data. We will examine the association between donor CTRA and related transcriptome dynamics and recipient allogeneic transplant outcomes - including disease-free survival, transplant-related mortality, relapse risk, graft-versus-host disease, and overall survival ? as well as the relationships between donor and recipient immunobiologic patterning on response to HCT. This translational study builds upon our prior research, explores the transplantable nature of donor sociodemographic factors on cancer biology, and lays the critical groundwork for interventions targeting SES-related donor health to improve cancer outcomes. In sum, the proposed work will further define our biologic mechanistic understanding of social health disparities in cancer.
Accumulating evidence indicates that low socioeconomic status (SES) in the hematopoietic cell transplantation (HCT) recipient is associated with adverse transplant outcomes, and recent data have shown that up- regulation of a stress-related immunologic gene expression profile in the transplant recipient may represent a socially-mediated biological explanation for this finding. Interestingly, allogeneic HCT involves the replacement of the recipient?s immune system with that of a healthy donor; this led to the current proposal in which we will explore the impact of donor SES and immunologic gene expression on recipient HCT outcomes. This research will significantly extend our understanding of the immunologic mechanisms and pathways underlying the comorbidity of social health disparities in cancer - particularly within the biologically unique setting of HCT ? and will provide a critical link for designing effective interventions to reduce cancer disparities.
