(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.

抽象的 具有高风险或复发性血液系统恶性肿瘤的患者可以使用同种异体造血性治愈 细胞移植（HCT）；但是，HCT具有死亡率的重大风险。我们的小组已经确定 在低社会经济地位（SES）的接受者中，这种风险较差。 HCT越来越多 用于治疗各种恶性肿瘤和血液学障碍，但社交广告继续考虑 这种癌症治疗的发病率和死亡率较高。我们以前已经确定了一个接收者 - 在不良同种异体HCT患者结局中实施的与SES相关的水平相关的免疫生物学因子 - 一种基因 表达模式称为“对广告的保守转录响应”（CTRA）。重要的 CTRA轮廓的组成部分是促炎性的。相度地，几个捐助者级特征是 对于预测同种异体HCT结果很重要。此外，供体细胞在接受者中植入 随后的造血是供体衍生的。尽管如此，尚不清楚供体免疫生物学是否 与SES会议相关的差异与HCT接收者相关的额外预后风险。这项研究的目标 项目是为了确定与SES相关的供体水平的免疫生物学风险因素HCT结果。这 该提案的主要目的是：1）量化捐助者SES如何改变受体HCT结果； 2）确定 供体SES与基因表达之间的关系以及供体基因表达对受体的影响 HCT结果； 3）评估供体和受体SES在临床结果上的相互作用并进行量化 供体和受体基因表达对临床结果的综合作用。我们的总体 假设是，供体中与SES相关的促炎基因表达模式将与 劣等受体HCT结果，这种效果将与受体基因表达模式有协同作用 影响接收者的结果。该研究计划采用分子生物学和免疫学技术 通过与联邦资助的合作来调查健康差异的免疫生物学因素 国际血液和骨髓移植研究中心（CIBMTR）。我们将利用 主要研究人员，共同研究人员和顾问的多学科团队使用临床（n = 2840） 和生物学（n = 184）HCT供体数据。我们将研究捐助者CTRA与相关的关联 转录组动力学和受体同种异体移植结果 - 包括无病生存， 与移植相关的死亡率，救济风险，移植物与宿主病和整体生存 - 以及 供体和受体免疫生物学对HCT反应的关系。这种翻译 研究以我们先前的研究为基础，探讨了供体社会人口统计学因素的可移植性质 癌症生物学，并为针对SES相关供体健康的干预措施奠定了重要的基础 癌症的结果。总而言之，拟议的工作将进一步定义我们对 癌症的社会健康差异。