Variation in tumor-associated immune profiles and colorectal cancer outcomes

肿瘤相关免疫反应在不同种族/民族人群中存在相当大的差异性。 这些变化可能解释了观察到的癌症治疗反应差异的部分原因，尤其是 免疫治疗和治疗结果。在结直肠癌中，肿瘤的强度和成分 浸润性淋巴细胞(TIL)是公认的预后和预测指标。然而，因素 在各区域中心中观察到的TIL反应多样性的原因在很大程度上仍不清楚，而且 种族/族裔和遗传血统的影响一直未得到充分探讨。在最近的一项比较CRC的研究中 从非洲裔美国人和非西班牙裔白人中，观察到淋巴细胞反应的差异 部分解释了两组之间的生存差距。没有其他种族/民族的数据 组。以前的研究也受到了限制，仅仅依靠自我报告的种族/民族，这是一个重要的 限制。研究表明，自我报告不能完全或准确地反映存在于 混杂的少数民族人口。我们假设祖先的遗传结构对塑造 根据观察到的免疫功能的不同效率，结直肠癌预后的免疫相关决定因素 跨种族/民族群体。对普遍混杂的拉丁裔群体的研究提供了显著的优势 包括一个独特的机会，可以同时梳理出多个祖先背景的贡献 (例如，非洲人、欧洲人、美洲原住民)对免疫功能的可变性有影响。在这里，我们将测试 遗传祖先与肿瘤相关T细胞差异独立相关的假说 造成儿童权利公约结果差异的概况(即在按种族和性别定义的人群中观察到的 根据基因血统)使用来自西班牙裔结直肠癌研究的现有资源，波多黎各 生物库、全面癌症护理方案和结直肠癌分子流行病学研究 。我们 将解决三个目标：(1)量化来自不同遗传祖先的Latinx人的CRC相关T细胞图谱 使用基于DNA和蛋白质的方法的背景；(2)调查 肿瘤中T细胞类型的遗传祖先、流行病学因素和临床变量 Latinx CRC的微环境；以及(3)Latinx和NHW之间CRC相关T细胞的比较 人口。这项研究在利用拉美裔祖先的多样性来理解 种族/民族、生殖系遗传学、肿瘤免疫生物学和癌症差异之间的关系。 结果将为理解导致不成比例的免疫因素提供新的途径 不同人群结直肠癌患者的治疗反应和死亡率。

Considerable variability in tumor-associated immune responses exists across racial/ethnic populations. These variations may explain part of the observed disparities in response to cancer therapies, particularly immunotherapy, and treatment outcomes. In colorectal cancer (CRC), the intensity and composition of tumor infiltrating lymphocytes (TIL) are established prognostic and predictive indicators. However, factors contributing to the diversity of TIL responses observed among CRCs remain largely unknown, and the influence of race/ethnicity and genetic ancestry have been underexplored. In a recent study comparing CRCs from African Americans and non-Hispanic Whites, differences in lymphocytic reactions were observed to partially explain the survival disparity between the two groups. No data is available for other racial/ethnic groups. Prior research has also been limited by relying solely on self-reported race/ethnicity, a significant limitation. Studies show that self-report does not fully or accurately reflect the genetic diversity present in admixed minority populations. We hypothesize that ancestral genetic architecture is important for shaping immune-related determinants of CRC outcomes given the differential efficiency of immune function observed across racial/ethnic groups. Studies in the genertically admixed Latinx population offer notable advantages including a unique opportunity to simultaneously tease out the contributions of multiple ancestral backgrounds (e.g. African, European, Indigenous American) to variability in immune function. Here, we will test the hypothesis that genetic ancestry is independently associated with differences in tumor-associated T cell profiles that contribute to CRC outcome disparities (i.e. observed across populations defined by ethnicity and by genetic ancestry) using existing resources from the Hispanic Colorectal Cancer Study, the Puerto Rico Biobank, the Total Cancer Care Protocol, and the Molecular Epidemiology of Colorectal Cancer Study . We will address three aims: (1) quantify CRC-associated T cell profiles in Latinxs from diverse genetic ancestral backgrounds using DNA- and protein-based approaches; (2) investigate the independent associations of genetic ancestry, epidemiologic factors, and clinical variables with T cell profiles in the tumor microenvironment of Latinx CRCs; and (3) compare CRC-associated T cell profiles between Latinx and NHW populations. This study is unique in leveraging the ancestral diversity of Latinos to understand the relationships between race/ethnicity, germline genetics, tumor immunobiology, and cancer disparities. Results will provide new avenues for understanding immunological factors contributing to disproportionate treatment response and mortality in diverse populations of patients with CRC.