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 最近在免疫治疗方面的突破，特别是免疫检查点抑制剂(ICIS)已经收到 FDA的批准，一直是肺癌治疗的一大进步。到目前为止，ICI的临床试验已经 非洲裔美国人患者的代表性很差(4%)；但在有限的可用数据中，非洲裔美国人 对ICIS的反应比白人更差。在这些疗法中，介导阻断PD-1、PD-1的抗体 L1和CTLA-4信号被用来逆转肿瘤介导的免疫抑制和增强抗肿瘤作用 然而，免疫活动对许多患者没有好处。ICI的实施主要是由 疾病的严重性，对传统治疗的抵抗力，以及肿瘤的特征，但没有普遍的 可靠的生物反应标志物。在迄今探索的潜在反应生物标记物中，PD-L1表达和 肿瘤突变负荷(TMB)已显示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 在两种动物模型和非小细胞肺癌患者的肿瘤中，干扰素信号是共同的驱动因素，其中表达 在这些与PD-L1相关的基因中，有不同的种族。此外，相对于白人患者的肿瘤，来自 非洲裔美国人更有可能表达抗体重链和轻链的成分，尽管 普通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 这些种群。富含B细胞的三级淋巴结构(TLS)最近被发现存在于 肺癌和其他癌症作为ICI反应的潜在生物标志物。重要的是，虽然患者之间的直接联系 生殖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相关性和在发病和/或严重程度上的种族差异 免疫介导的疾病。我们的临床前研究结果显示，在遗传上对ICIS有广泛的应答率 携带相同基因肿瘤的不同小鼠，表明宿主基因调控因素可能控制抗肿瘤 豁免权。在这项研究中，我们将在前期工作的基础上，开发与种族特异性相关的免疫图谱 随着干扰素信号/PD-L1的表达和富含B细胞的TLS的存在和功能的变化，我们将确定 这些配置文件推动了对ICIS的响应。考虑到很少有非洲裔美国人被纳入ICI早期试验，这是 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 确定新的治疗目标，以减少肺癌结果的差异。