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.

概括 肺癌是Wake Forest Baptist综合癌症中心的第一大癌症诊断 （WFBCCC）。我们的癌症健康公平办公室发现，我们地区的非裔美国人（AAS）有 发病率和死亡率分别高15.1％和15.5％，高于已经升高的肺癌 美国AAS的比率了解我们患者的健康差异，其中14％是AA，并且 识别可以克服它们的有针对性的治疗剂是WFBCCC的首要任务之一，一致 如Par-18-655所述的NCI任务。临床上，免疫检查点阻滞（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 与高加索裔美国人（CA）患者相比，对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，我们研究了 使用最先进的单细胞在AAS和CAS之间浸润免疫肿瘤微环境（TME） RNA测序（SCRNA-SEQ）。对NSCLC患者的4个CA和4个AA样品的初步分析 显示两个种族群体之间的免疫TME明显差异。肿瘤中的体突变 细胞在免疫调节以及肿瘤细胞与TME之间的相互作用中起重要作用。具体的 肿瘤中的遗传突变可能会影响免疫景观，因此与癌症相关 差异。例如，我们最近报道了AA中TP53突变率和肿瘤突变负担更高 癌症患者。在这个项目中，我们建议用较大的数据来验证这些初步观察 肺癌患者队列。特定的目标1将表征和对比AA和CA的TME景观 NSCLC患者。将使用SCRNA-SEQ收集和剖析两个种族的其他样本 技术。特定的目标2将产生患者样本的突变曲线，目的 将特定的突变事件或突变模式与特定的免疫TME（SA1）相关联 病人种族。我们的总体假设是，NSCLC患者的AA患者的免疫抑制性TME具有 是导致种族健康差异的一个因素，但可能会被新的基于ICB的差异克服 免疫疗法。该发展性R21的数据和观察结果将在 正在进行的临床协会研究。该建议还将为 AA少数NSCLC人群，可用于癌症研究领域。总共提议 研究有可能使服务不足的患者人群受益，并为产生的基础提供了基础 关于未来R01关于肺癌健康差异的建议的假设。