Clinically Actionable Neoantigens in Non-Small Cell Lung Cancer

非小细胞肺癌临床上可行的新抗原

• 批准号: 9348557
• 负责人: Steven M. Dubinett
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2021-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9348557
• 关键词: Adenocarcinoma; Adoptive Cell Transfers; Affect; Antigen-Presenting Cells; Antigens; Area; Asbestos; Atypical adenomatous hyperplasia; Autologous; Beryllium; Binding; Biological Assay; CD8-Positive T-Lymphocytes; Cancer Etiology; Cause of Death; Cells; Cellular Immunity; Cessation of life; DNA sequencing; Data; Databases; Development; Disease; Effector Cell; Environmental Exposure; Exposure to; Future; Gene Expression; Genes; Histologic; Immune; Immune checkpoint inhibitor; Immune response; Immunohistochemistry; Immunosuppression; Immunotherapy; Incidence; Individual; Infiltration; Institute of Medicine (U.S.); Intercept; Interruption; Kerosene; Knowledge; Lasers; Lead; Lesion; Lobectomy; Lung; Lung Adenocarcinoma; Maintenance; Malignant neoplasm of lung; Mechanics; Military Personnel; Molecular; Mutation; Non-Small-Cell Lung Carcinoma; Oils; Operative Surgical Procedures; Pathogenesis; Patients; Phase; Population; Premalignant; Prevention; Primary Neoplasm; Proteins; Radon; Research; Resources; Risk; Risk Factors; Smoke; Smoking; Source; Specimen; Stains; Structure of parenchyma of lung; T-Lymphocyte; The Cancer Genome Atlas; Tissues; Tobacco use; Uranium; Vaccines; Veterans; Work; Workload; Workplace; agent orange; cancer invasiveness; clinically actionable; combustion product; cooking; disease natural history; exhaust; exome; high risk; imaging study; improved; nano-string; neoantigens; peripheral blood; response; screening; targeted treatment; therapy outcome; tumor; tumor progression; vaccine development; weapons

Clinically actionable neoantigens in non-small cell lung cancer Lung cancer is the leading cause of cancer death among US Veterans as well as the world's leading cause of cancer death. Environmental exposure and tobacco use among Veterans operate together to increase risk. Unleashing the immune response against pulmonary premalignancy could transform therapy and outcomes. Here, we propose to lay the ground work for lung “cancer interception,” a strategy that seeks to block the progression of premalignancy to invasive cancer. In our preliminary studies we have begun to evaluate the mutational landscape of pulmonary premalignancy and the associated premalignant microenvironment by whole exome DNA sequencing and immunohistochemistry. Remarkably, we find frequent immune-effector cell infiltration as well as evidence of immune suppression in pulmonary premalignancy. These findings lead us to hypothesize that premalignant-associated neoantigens (PANs) are recognized and elicit immune responses at the earliest points of lung adenocarcinoma development. This research will identify neoepitopes that can be targeted before the development of invasive lung cancer, thus shifting the approach to disease interception through immunoprevention and treatment of the very earliest phase of the disease. The specific aims are: 1) To utilize whole exome DNA sequencing (WES) to determine computationally-defined neoantigens in matched sets of primary tumor, premalignant lesions and adjacent histologically normal lung tissues. 2) To identify functionally relevant neoepitopes associated with tumor progression: Two sources of T cells, one from TIL, the other from peripheral blood PD1+ T cells, will be used to identify neoepitope-specific CD8+ T cells. To improve screening efficiency, we will focus on neoantigens shared between pre-malignant lesions and primary tumors that are potentially progression-relevant. Functional assays will be performed to verify the identified neoepitopes. This will lead to patient-tailored neoepitopes for future vaccine or adoptive cell therapies for non-small cell lung cancer (NSCLC). 3) To relate the immune contexture to WES-defined mutational landscapes in premalignancy and the associated tumor we will: 3A) Perform quantitative multiplexed immunofluorescent staining of the same specimens utilized in the first two aims to assess the regulators of cell- mediated immunity and to relate this to the mutational landscapes and neoepitopes of the premalignant lesions and tumors, 3B) Evaluate gene expression utilizing a Nanostring panel of 770 immune-related genes and, 3C) Integrate findings from WES, gene expression and tissue immunostaining to define the landscape of adenocarcinoma pulmonary premalignancy. This research seeks to transform the approach to both the prevention and treatment of lung adenocarcinoma by discovery of functional neoepitopes that can be utilized in the development of vaccines and adoptive therapies to intercept disease at the earliest phases. With the advent of screening, many patients are presenting with imaging studies consistent with focal or multifocal premalignancy. As we increase our knowledge of the molecular pathogenesis and natural history of the disease, discovery of critical neoepitopes will facilitate vaccine development for those at the highest risk for progression to invasive lung cancer.

临床上可起作用的新抗原在非校友细胞肺癌中 肺癌是美国退伍军人中癌症死亡的主要原因，同样是世界的主要原因 癌症死亡。 释放针对肺部预现态的免疫反应可以改变治疗和结局。 在这里，我们建议为肺“癌症截距”奠定基础工作，该策略试图阻止您 对侵入性癌症的进展。 肺前期的突变景观和相关的预立剂 外部DNA测序和免疫组织化学。 浸润和肺部预抑制的证据使我们得以实现。 假设与预立剂相关的新抗原（PAN）被认识到，并在 肺腺癌开发的最早要点。 在侵入性肺癌发展之前针对疾病截止 通过免疫预防和治疗该疾病的原始阶段。 具体目的是：1）利用整个外显子组DNA测序（WES）来确定计算定义 在匹配的原发性肿瘤，预立毒性病变和牙入的匹配集中的新抗原 组织2）确定与肿瘤进展相关的功能相关的新型 一个来自TIL的细胞，另一个来自外周血PD1+ T细胞的细胞将用于鉴定新EPITOPE特异性 CD8+ T细胞。 潜在的进展与功能分析的病变和原发性肿瘤。 验证已识别的新发表型。 非小细胞肺癌的疗法（NSCLC）。 前期和相关肿瘤中的景观我们将：3a）执行定量多路复用 前两个使用的相同标本的免疫荧光染色评估了细胞的调节剂 介导的IMNITY并关联了预立衰变的突变景观和新斑点 和肿瘤，3B）利用770个免疫相关基因和3C的纳米弦面板评估基因表达利用率 整合WES，基因表达和组织免疫染色的发现，以定义 腺癌肺部预先抗衡。 通过发现可以促进的功能性新发出的预防和治疗肺腺癌的治疗 在最早的疫苗中开发疫苗和收养疾病 筛查时，许多患者正在进行与局灶性或多灶一致的成像研究 当我们增加对疾病的分子发病机理的了解时， 发现关键的新发表将面临最高风险的人的疫苗疫苗开发 侵入性肺癌。