Tumor microenvironment at single cell level in black and white NSCLC patients

黑人和白人 NSCLC 患者单细胞水平的肿瘤微环境

• 批准号: 10057810
• 负责人: Liang Liu
• 金额: $ 39.85万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10057810
• 关键词: Affect; African American; Appalachian Region; Baptist Church; Biological Factors; CD8-Positive T-Lymphocytes; CTLA4 gene; Cancer Patient; Catchment Area; Cells; Cellular Structures; Clinical; Clinical Data; Cohort Studies; Comprehensive Cancer Center; DNA Sequence Alteration; DNA sequencing; Data; Data Set; Development; Ecosystem; Epigenetic Process; Ethnic Origin; Event; Face; Future; Immune; Immunotherapy; Incidence; Inferior; Institution; Intelligence; Light; Lung Neoplasms; Lymphocyte; Malignant Neoplasms; Malignant neoplasm of lung; Minority; Mission; Molecular; Mutation; Myelogenous; Myeloid Cells; Natural Killer Cells; Non-Small-Cell Lung Carcinoma; Nonmetastatic; North Carolina; Outcome; Patients; Pattern; Pharmaceutical Preparations; Pharmacotherapy; Pilot Projects; Play; Population; Progression-Free Survivals; Publications; Race; Reporting; Resources; Role; Sampling; Smoker; Smoking; Somatic Mutation; T-Lymphocyte; TP53 gene; Techniques; Technology; Testing; Tobacco Industry; Treatment Protocols; Tumor-infiltrating immune cells; Validation; anticancer research; base; bioinformatics pipeline; cancer diagnosis; cancer health disparity; cancer type; caucasian American; cohort; design; effective therapy; exhaust; exome; experience; forest; health disparity; health equity; immune checkpoint blockade; immunoregulation; immunosuppressed; improved; insight; mortality; multidisciplinary; mutational status; neoplastic cell; next generation sequencing; patient population; patient response; profiles in patients; programs; racial disparity; racial health disparity; response; single-cell RNA sequencing; targeted treatment; treatment disparity; tumor; tumor microenvironment; tumor-immune system interactions

Summary Lung cancer is the number one cancer diagnosis at Wake Forest Baptist Comprehensive Cancer Center (WFBCCC). Our Office of Cancer Health Equity found that African Americans (AAs) in our region have incidence and mortality rates 15.1% and 15.5% higher, respectively, than the already elevated lung cancer rates among AAs in the U.S. Understanding health disparities in our patients, 14% of whom are AA, and identifying targeted therapeutics that can overcome them are among the top priorities of WFBCCC, consistent with the stated mission of NCI as described in PAR-18-655. Clinically, immune checkpoint blockade (ICB) drug treatment can benefit 30% of non-small cell lung cancer (NSCLC) patients. At WFBCCC, AA patients have a relatively better response to ICB compared to Caucasian American (CA) patients, suggesting ICB has the potential to eliminate cancer disparities. To gain insight into this clinical observation we investigated the infiltrating immune tumor microenvironment (TME) between AAs and CAs using the state-of-the-art single cell RNA sequencing (scRNA-Seq). Preliminary analysis of 4 CA and 4 AA samples from patients with NSCLC showed marked difference in the immune TME between the two racial groups. Somatic mutations in tumor cells play important roles in immune regulation and the interactions between tumor cells and TME. Specific genetic mutations in the tumor may impact the immune landscape, and consequently associate with cancer disparities. For example, we recently reported a higher TP53 mutation rate and tumor mutation burden in AA cancer patients. In this project, we propose to validate these preliminary observations with data from a larger cohort of lung cancer patients. Specific aim 1 will characterize and contrast the TME landscapes of AA and CA patients with NSCLC. Additional samples from both races will be collected and profiled using the scRNA-Seq technique. Specific aim 2 will generate the mutation profiles of the patient samples with the objective to associate specific mutational events, or patterns of mutations, with the characterized immune TME (SA1) by patient race. Our overarching hypothesis is that an immunosuppressive TME in AA patients with NSCLC has been a contributing factor to racial health disparities, but may be overcome by newer ICB-based immunotherapies. The data and observations from this developmental R21 will be interpreted in the context of the ongoing clinical association studies. This proposal will also produce a valuable scRNA-Seq dataset for the AA minority NSCLC population and be made available to the cancer research field. Altogether, the proposed study has the potential to benefit an underserved patient population and provide a basis for generating hypotheses for future R01 proposals on lung cancer health disparities.

总结 肺癌是维克森林浸信会综合癌症中心的头号癌症诊断 （WFBCCC）。我们的癌症健康公平办公室发现，我们地区的非洲裔美国人（AAs） 发病率和死亡率分别比已经升高的肺癌高15.1%和15.5% 了解我们患者的健康差异，其中14%是AA，以及 确定可以克服这些问题的靶向治疗方法是WFBCCC的首要任务之一， 与PAR-18-655中所述的NCI声明的使命一致。临床上，免疫检查点阻断（ICB）药物 治疗可以使30%的非小细胞肺癌（NSCLC）患者受益。在WFBCCC，AA患者有 与白人美国（CA）患者相比，ICB的反应相对更好，这表明ICB具有 消除癌症差异的潜力。为了深入了解这一临床观察，我们调查了 使用最先进的单细胞技术在AA和CA之间浸润免疫肿瘤微环境（TME） RNA测序（scRNA-Seq）。4例非小细胞肺癌CA和4例AA标本的初步分析 两个种族之间的免疫TME存在显著差异。肿瘤的体细胞突变 细胞在免疫调节和肿瘤细胞与TME之间的相互作用中起重要作用。具体 肿瘤中的基因突变可能会影响免疫系统，因此与癌症有关。 差距。例如，我们最近报道了AA中TP 53突变率和肿瘤突变负荷较高， 癌症患者。在这个项目中，我们建议用来自一个更大的实验室的数据来验证这些初步观察结果。 肺癌患者的队列。具体目标1将描述和对比AA和CA的TME景观 NSCLC患者。将收集来自两个种族的额外样本，并使用scRNA-Seq 法具体目标2将生成患者样本的突变谱，目的是 通过以下方式将特定突变事件或突变模式与表征的免疫TME（SA 1）相关联： 耐心的比赛我们的总体假设是，在患有NSCLC的AA患者中， 是种族健康差异的一个促成因素，但可能会被新的基于ICB的 免疫疗法从这一发展的R21的数据和观察将解释的背景下， 正在进行的临床关联研究。该提案还将为研究人员提供有价值的scRNA-Seq数据集。 AA少数NSCLC人群，并可用于癌症研究领域。总的来说， 这项研究有可能使服务不足的患者群体受益，并为产生 关于肺癌健康差异的未来R 01提案的假设。