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

摘要 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，我们地区的非裔美国人(AA) 发病率和死亡率分别比已经升高的肺癌高出15.1%和15.5% 了解我们患者的健康差距，其中14%是再障患者，以及 确定可以克服这些障碍的靶向疗法是WFBCCC的首要任务之一，始终如一 与PAR-18-655中所述的NCI的既定任务。临床上，免疫检查点阻断(ICB)药物 治疗可使30%的非小细胞肺癌(NSCLC)患者受益。在WFBCCC，AA患者有一个 与高加索美国人(CA)患者相比，ICB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，我们调查了 应用最先进的单细胞技术在AAS和CA之间侵袭免疫肿瘤微环境(TME) RNA测序(scRNA-Seq)。4例非小细胞肺癌患者CA和AA标本的初步分析 免疫TME在两个种族间有显著差异。肿瘤中的体细胞突变 细胞在免疫调节以及肿瘤细胞与TME的相互作用中发挥着重要作用。特定的 肿瘤中的基因突变可能会影响免疫状况，因此与癌症有关。 差距。例如，我们最近报道了再生障碍性贫血患者较高的TP53突变率和肿瘤突变负担。 癌症患者。在这个项目中，我们建议用一个更大的数据来验证这些初步观察。 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 非小细胞肺癌患者。将收集来自两个种族的额外样本，并使用scRNA-Seq进行分析 技术。特定目标2将生成患者样本的突变图谱，目的是 通过以下方式将特定的突变事件或突变模式与表征的免疫性TME(SA1)相关联 耐心的赛跑。我们的主要假设是免疫抑制剂TME对患有非小细胞肺癌的AA患者具有 是种族健康差距的一个促成因素，但可能会被较新的基于ICB的 免疫疗法。来自R21发育期的数据和观察结果将在以下背景下解释 正在进行的临床关联研究。这项提议还将产生一个有价值的scRNA-Seq数据集 AA少数民族非小细胞肺癌人群，并可用于癌症研究领域。总而言之，建议的 这项研究有可能造福于服务不足的患者群体，并为 未来关于肺癌健康差异的R01提案的假设。

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.