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

摘要 高危或复发的恶性血液病患者可使用异基因造血系统治愈 细胞移植(HCT)；然而，HCT有很大的死亡风险。我们小组已经确认 这种风险在低社会经济地位(SES)的接受者中更是不成比例地严重。Hct越来越多地 用于治疗各种恶性肿瘤和血液病，但社会逆境继续占主导地位 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名收件人- SES相关免疫生物学因子水平与异基因HCT患者不良结局相关--A基因 表达模式称为“逆境保守转录反应”(CTRA)。一个重要的 CTRA档案的成分是促炎的。反过来，捐赠者级别的几个特征是 在预测异基因血细胞移植结局方面具有重要意义。此外，供体细胞植入受者体内，从而 随后的造血是来自捐赠者的。尽管如此，目前尚不清楚捐赠者的免疫生物学 与SES相关的差异给HCT接受者带来了额外的预后风险。这项研究的目的是 该项目是确定与SES相关的供体水平的免疫生物学危险因素，以导致不良的HCT结局。这个 该提案的主要目的是：1)量化捐赠者SES如何改变受者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)评估供者和受者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联合影响。我们最重要的是 假设SES相关的促炎基因在捐献者中的表达模式将与 较差的受体HCT结果，这种影响将与受体基因表达模式协同作用 在影响受赠者的结果方面。该研究计划采用了分子生物学和免疫学技术。 通过与联邦基金合作调查健康差异背后的免疫生物学因素 国际血液和骨髓移植研究中心(CIBMTR)我们将利用 由首席调查人员、合作调查人员和顾问组成的多学科团队，使用临床(N=2840) 和生物学(N=184)HCT捐献者数据。我们将检查捐赠者CTRA和相关的 转录组动力学和受者异基因移植结果--包括无病存活， 与移植相关的死亡率、复发风险、移植物抗宿主病和总存活率-以及 供受者的免疫生物学模式与红细胞移植反应的关系。此翻译 这项研究建立在我们之前的研究基础上，探索了捐赠者社会人口因素的可移植性质 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 癌症后果。总之，拟议的工作将进一步定义我们对 癌症方面的社会健康差异。

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.