Project 1

项目1

• 批准号: 10289603
• 负责人: Ann G. Schwartz
• 金额: $ 31.41万
• 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/10289603
• 关键词: Address; African American; 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; Nonmetastatic; 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; base; biomarker discovery; cancer diagnosis; cancer health disparity; cancer immunotherapy; cancer therapy; chemotherapy; cohort; disparity reduction; environmental tobacco smoke exposure; health disparity; immunotherapy trials; improved; improved outcome; inhibitor/antagonist; 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.

项目摘要 最近的免疫疗法的突破，特别是接受的免疫检查点抑制剂（ICI） FDA批准是肺癌治疗的重大进步。到目前为止，ICI临床试验已经 非裔美国人患者的代表性不佳（<4％）；但是在有限的数据中，非洲裔美国人 对ICI的反应比白人表现得更差。在这些疗法中，介导PD-1，PD-的封锁的抗体 L1和CTLA-4信号传导用于反向肿瘤介导的免疫抑制和增强抗肿瘤 但是，免疫活性，许多患者无法受益。 ICI实施主要由 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 可靠的反应生物标志物。迄今为止探索的潜在反应生物标志物，PD-L1表达和 肿瘤突变负担（TMB）表现出适度但不完整的预测ICI结局的能力。我们的 初步研究确定了与PD-L1表达相关的免疫基因的子集，其中干扰素 （IFN）信号传导是一种常见的驱动力，在动物模型和NSCLC患者的肿瘤中，在其中表达 这些与PD-L1相关的基因在种族方面有所不同。此外，相对于白人患者的肿瘤，来自 尽管类似 一般B细胞标记的表达，这可能表明来自肿瘤内B细胞的功能差异 这些人群。最近在 肺部和其他癌症是ICI反应的潜在生物标志物。重要的是，患者之间的直接联系 种系遗传学和对免疫疗法的反应仍然难以捉摸，数十年的自身免疫性和炎症 研究已经确定了几种发作和/或严重性的宿主基因组关联和种族差异 免疫介导的疾病。我们的临床前发现揭示了遗传学上对ICI的较广泛的响应率 带有遗传相同肿瘤的各种小鼠，表明宿主遗传调节剂可能控制抗肿瘤 免疫。在这项研究中，我们将以我们的初步工作为基础，以开发针对种族特定的免疫特征 使用IFN信号传导/PD-L1的表达以及富B细胞的TLS的存在和功能，我们将确定是否确定 这些配置文件推动对ICIS的响应。考虑到很少有非洲裔美国人被包括在ICI早期试验中，这是 对独特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 确定肺癌预后差异降低的新型治疗靶标。