(PQ2) Donor socioeconomic status as a predictor of altered immune function and treatment response following hematopoietic cell transplantation for hematologic malignancy

(PQ2) 捐献者社会经济状况可作为血液恶性肿瘤造血细胞移植后免疫功能和治疗反应改变的预测因子

• 批准号: 10239032
• 负责人: Jennifer Mary KNIGHT
• 金额: $ 35.4万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-11 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10239032
• 关键词: Acute Graft Versus Host Disease; Address; Affect; Allogenic; Angiogenic Factor; Biological; Biological Factors; Blood; Bone Marrow Transplantation; Cancer Biology; Cells; Characteristics; Clinical; Data; Disease-Free Survival; Donor person; Engraftment; Follistatin; Foundations; Funding; Future; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Genomics; Goals; Health; Health Services Accessibility; Hematologic Neoplasms; Hematological Disease; Hematopoiesis; Homologous Transplantation; Immune; Immune system; Immunogenetics; Immunologic Techniques; Immunologics; Individual; Inferior; Inflammation; Inflammatory; Insurance Coverage; Intervention; Lead; Leukocytes; Link; Malignant Neoplasms; Mediating; Methodology; Molecular Biology; Morbidity - disease rate; Nature; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Pattern; Principal Investigator; Process; Proteins; Race; Relapse; Research; Research Personnel; Research Project Grants; Risk; Risk Factors; Social Processes; Socioeconomic Status; Stress; Sum; Transplant Recipients; Transplantation; Treatment outcome; Up-Regulation; Work; base; cancer health disparity; cancer therapy; cohort; comorbidity; design; disadvantaged background; effective intervention; follow-up; graft vs host disease; health disparity; hematopoietic cell transplantation; high risk; immune function; improved; improved outcome; innovation; international center; leukemia; low socioeconomic status; mortality; mortality risk; multidisciplinary; novel strategies; prognostic; psychobiologic; relapse risk; response; social; social disparities; sociodemographic factors; sociodemographics; socioeconomic disadvantage; transcriptome; translational study; treatment response

ABSTRACT 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.

摘要 高风险或复发性恶性血液病患者可以使用同种异体造血干细胞移植治愈。 细胞移植（HCT）;然而，HCT具有显著的死亡风险。我们的小组已经确定， 这种风险在社会经济地位低的接受者中尤为严重。HCT越来越 用于治疗各种恶性肿瘤和血液病，但社会逆境继续占 这种癌症治疗的发病率和死亡率更高。我们之前已经确认了一个接收者- 与异基因HCT患者不良结局相关SES相关免疫生物学因子水平--一种基因 这种表达模式被称为“逆境保守转录反应”（CTRA）。显著 CTRA特征的组成部分是促炎性的。反过来，捐助方一级的若干特点是 在预测同种异体HCT结果方面具有重要意义。此外，供体细胞移植到受体中，使得 随后的造血是供体来源的。尽管如此，尚不清楚供体免疫生物学是否 与SES相关的差异赋予HCT接受者额外的预后风险。本研究的目的 该项目的目的是确定与SES相关的供者水平的免疫生物学危险因素，从而导致不利的HCT结果。的 该提案的主要目的是：1）量化供体SES如何改变受体HCT结果; 2）确定 供体SES与基因表达的关系及供体基因表达对受体的影响 HCT结果;以及3）评估供体和受体SES对临床结果的相互作用，并量化 供体和受体基因表达对临床结果的综合影响。我们的总体 一种假设是，在供体中SES相关的促炎基因表达模式将与 较低的受体HCT结果，并且这种效应将与受体基因表达模式协同作用 影响接受者的结果。研究计划采用分子生物学和免疫学技术 通过与联邦资助的 国际血液和骨髓移植研究中心（CIBMTR）我们将利用 由主要研究者、合作研究者和顾问组成的多学科团队，使用临床（N=2840） 和生物学（N=184）HCT供体数据。我们将研究供体CTRA和相关的 转录组动力学和受体同种异体移植结果-包括无病生存， 移植相关死亡率、复发风险、移植物抗宿主病和总生存率，以及 供体和受体免疫生物学模式对HCT应答的关系。这种平移 这项研究建立在我们以前的研究基础上，探讨了捐赠者社会人口因素的可移植性， 癌症生物学，并为针对SES相关捐赠者健康的干预措施奠定了关键基础， 癌症结果。总之，这项工作将进一步确定我们对生物学机制的理解， 癌症中的社会健康差异。