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.

项目摘要 最近免疫治疗的突破，特别是免疫检查点抑制剂（ICI）， FDA的批准是肺癌治疗的一个重大进步。到目前为止，ICI临床试验已经 非裔美国人患者的代表性较差（<4%）;但在有限的可用数据中，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-2、PD-3和PD-4的阻断的抗体可用于治疗PD-1、PD-3和PD-4的抑制。 L1和CTLA-4信号传导被用于逆转肿瘤介导的免疫抑制和增强抗肿瘤作用。 然而，免疫活性，许多患者未能受益。ICI的实施主要遵循以下原则： 疾病的严重程度，对传统治疗的抵抗力，以及肿瘤的特征，但没有普遍的 可靠的反应生物标志物。在迄今为止探索的潜在缓解生物标志物中，PD-L1表达和 肿瘤突变负荷（TMB）显示出中等但不完全的预测ICI结果的能力。我们 初步研究确定了一个与PD-L1表达相关的免疫基因子集，其中干扰素 (IFN)在动物模型和NSCLC患者的肿瘤中，信号传导是一个共同的驱动因素， 这些PD-L1相关基因的差异因种族而异。此外，相对于来自白色患者的肿瘤，来自 非裔美国人更有可能表达抗体重链和轻链的成分，尽管类似的 一般B细胞标志物的表达，这可能表明肿瘤内B细胞与肿瘤内B细胞的功能差异。 这些人口。最近发现，在淋巴结中存在富含B细胞的三级淋巴样结构（TLS）。 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协会和种族差异的发病和/或严重程度， 免疫介导的疾病。我们的临床前研究结果显示，在遗传学上， 不同的小鼠携带遗传相同的肿瘤，这表明宿主遗传调节因子可能控制抗肿瘤 免疫力在这项研究中，我们将建立在我们的初步工作，以开发种族特异性免疫概况相关 IFN信号转导/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 这些分布驱动对ICI的响应。考虑到早期ICI试验中很少有非洲裔美国人， 对不同的免疫特征及其与结果的关系进行全面评价至关重要 在不同的人群中。这些研究的结果有可能指导治疗决策， 确定新的治疗靶点，以减少肺癌结果的差异。