Project 1

项目1

• 批准号: 10684279
• 负责人: Ann G. Schwartz
• 金额: $ 28.79万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10684279
• 关键词: Address; African American; African American population; Animal Model; Antibodies; Autoimmunity; Automobile Driving; B-Lymphocytes; Biological Markers; CTLA4 gene; Cancer Patient; Cell physiology; Chemotherapy and/or radiation; Clinical; Clinical Trials; Consolidation Therapy; Core Biopsy; Coupled; DNA Sequence Alteration; Data; Decision Making; Disease; Environment; Evaluation; Exhibits; FDA approved; Genes; Genetic; Genetic Variation; Genomic DNA; Genomics; Goals; Histologic; Human; Immune; Immune Targeting; Immune checkpoint inhibitor; Immunologic Markers; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Incidence; Inflammation; Interferons; Light; Link; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Mus; Mutation; Non-Small-Cell Lung Carcinoma; Outcome; PD-1 blockade; Pathway interactions; Patients; Phenotype; Platinum; Population; Population Heterogeneity; Race; Research; Resistance; Role; Sampling; Series; Severities; Severity of illness; Signal Transduction; Surrogate Markers; Transcript; Tumor Immunity; Unresectable; Variant; Work; biomarker discovery; cancer diagnosis; cancer health disparity; cancer immunotherapy; cancer therapy; chemotherapy; cohort; disparity reduction; environmental tobacco smoke exposure; immunotherapy trials; improved; improved outcome; inhibitor; new therapeutic target; potential biomarker; pre-clinical; predicting response; programmed cell death ligand 1; programmed cell death protein 1; prospective; racial disparity; racial diversity; response; response biomarker; specific biomarkers; tertiary lymphoid organ; transcriptomics; treatment response; treatment trial; tumor

Project Summary The recent breakthroughs in immunotherapy, particularly immune checkpoint inhibitors (ICIs) that have received FDA approval, have been a major advancement for lung cancer treatment. Thus far, ICI clinical trials have had poor representation from African American patients (<4%); but in the limited data available, African Americans show poorer response to ICIs than whites. In these therapies, antibodies that mediate the blockade of PD-1, PD- L1, and CTLA-4 signaling are utilized to both reverse tumor-mediated immune suppression and boost anti-tumor immune activity, however, many patients fail to benefit. ICI implementation has been guided predominantly by disease severity, resistance to traditional treatments, and features of the tumor, but there are no universally reliable biomarkers of response. Of the potential response biomarkers explored to date, PD-L1 expression and tumor mutational burden (TMB) have exhibited moderate, yet incomplete capacity to predict ICI outcomes. Our preliminary studies identified a subset of immune genes that associate with PD-L1 expression, where interferon (IFN) signaling is a common driver, in both animal models and in tumors from NSCLC patients, where expression of these PD-L1-associated genes differs by race. Additionally, relative to tumors from white patients, tumors from African Americans were more likely to express components of antibody heavy and light chains, despite similar expression of general B cell markers, which may indicate a functional difference in intratumoral B cells from these populations. The presence of B cell-rich tertiary lymphoid structures (TLS) have recently been identified in lung and other cancers as a potential biomarker for ICI response. Importantly, while a direct link between patient germline genetics and response to immunotherapy remains elusive, decades of autoimmunity and inflammation research have identified host genomic associations and racial disparities in the onset and/or severity of several immune-mediated diseases. Our preclinical findings reveal a wide range of response rates to ICIs in genetically diverse mice bearing genetically identical tumors, suggesting host genetic regulators may govern anti-tumor immunity. In this study, we will build on our preliminary work to develop race-specific immune profiles associated with IFN signaling/PD-L1 expression and presence and function of B cell-rich TLS, and we will determine whether these profiles drive response to ICIs. Considering few African Americans were included in early ICI trials, it is critical to conduct a comprehensive evaluation of the distinct immune profiles and their relationship to outcomes in diverse populations. Results from these studies have the potential to guide treatment decision-making and identify novel therapeutic targets for reduced disparities in lung cancer outcomes.

项目概要 免疫治疗的最新突破，特别是免疫检查点抑制剂（ICIs） FDA 的批准是肺癌治疗的重大进步。迄今为止，ICI临床试验已 非裔美国患者的代表性较差（<4%）；但根据现有的有限数据，非裔美国人 对 ICI 的反应比白人差。在这些疗法中，介导 PD-1、PD- 阻断的抗体 L1 和 CTLA-4 信号传导可逆转肿瘤介导的免疫抑制并增强抗肿瘤作用 然而，许多患者未能从免疫活性中受益。 ICI 的实施主要以 疾病的严重程度、对传统治疗的抵抗力以及肿瘤的特征，但没有普遍适用的标准 可靠的反应生物标志物。在迄今为止探索的潜在反应生物标志物中，PD-L1 表达和 肿瘤突变负荷（TMB）表现出中等但不完全的预测 ICI 结果的能力。我们的 初步研究确定了与 PD-L1 表达相关的免疫基因子集，其中干扰素 (IFN) 信号传导是动物模型和 NSCLC 患者肿瘤中的常见驱动因素，其中表达 这些 PD-L1 相关基因的数量因种族而异。此外，相对于白人患者的肿瘤，来自白人患者的肿瘤 非裔美国人更有可能表达抗体重链和轻链的成分，尽管相似 一般 B 细胞标志物的表达，这可能表明肿瘤内 B 细胞的功能差异 这些人群。最近在 B 细胞中发现了富含 B 细胞的三级淋巴结构 (TLS) 的存在 肺癌和其他癌症作为 ICI 反应的潜在生物标志物。重要的是，虽然患者之间存在直接联系 种系遗传学和对免疫治疗的反应仍然难以捉摸，数十年的自身免疫和炎症 研究已经确定了宿主基因组关联和几种疾病的发病和/或严重程度的种族差异 免疫介导的疾病。我们的临床前研究结果揭示了遗传性 ICI 的广泛反应率 不同的小鼠携带遗传相同的肿瘤，表明宿主遗传调节剂可能控制抗肿瘤 免疫。在这项研究中，我们将在我们的初步工作的基础上开发相关的种族特异性免疫特征 IFN 信号传导/PD-L1 表达以及富含 B 细胞的 TLS 的存在和功能，我们将确定是否 这些配置文件推动了对 ICI 的响应。考虑到早期 ICI 试验中纳入的非洲裔美国人很少， 对不同的免疫特征及其与结果的关系进行全面评估至关重要 在不同的人群中。这些研究的结果有可能指导治疗决策和 确定新的治疗靶点以减少肺癌结果的差异。