Project 1

项目1

• 批准号: 10491106
• 负责人: Ann G. Schwartz
• 金额: $ 51.72万
• 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/10491106
• 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; 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; 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.

项目总结