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.

非小细胞肺癌中临床上可起作用的新抗原 肺癌是美国退伍军人中癌症死亡的主要原因，以及世界上的主要原因 癌症死亡。退伍军人之间的环境风险和烟草使用共同运作以增加风险。 释放针对肺部预先记录的免疫响应可以改变治疗和结果。 在这里，我们建议为肺部“癌症截距”奠定基础工作，该策略旨在阻止该策略 侵入性癌症预先命名的进展。在我们的初步研究中，我们已经开始评估 肺部预现态的突变景观和相关的预谨慎微环境。 外部DNA测序和免疫组织化学。值得注意的是，我们经常发现免疫效应细胞 浸润以及肺前抑制的证据。这些发现使我们进入 假设与预立剂相关的新抗原（PANS）被认识到，并引起免疫反应 肺腺癌发育的最早点。这项研究将确定可能是 在侵入性肺癌发展之前针对的目标，从而改变了疾病拦截的方法 通过免疫预防和治疗该疾病的早期阶段。 具体目的是：1）使用整个外显子组DNA测序（WES）来确定计算定义 在匹配的原发性肿瘤，预立毒性病变和相邻组织学正常肺的新抗原 组织。 2）识别与肿瘤进展相关的功能相关的新垂体：t的两个来源 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Neoeppitope特异性 CD8+ T细胞。为了提高筛选效率，我们将重点介绍新抗原的新抗原 可能与进展相关的病变和原发性肿瘤。功能测定将进行 验证已识别的Neoeppitopes。这将导致对未来疫苗或适应性细胞的患者调节的培训 非小细胞肺癌（NSCLC）的疗法。 3）将免疫环境与WES定义的突变联系起来 预先记录和相关肿瘤中的景观：3A）执行定量多路复用 在前两个目的中使用的相同标本的免疫荧光染色用于评估细胞的调节剂 介导的免疫力并将其与前病变的突变景观和新垂体相关联 和肿瘤，3B）使用770个免疫相关基因的纳米串面板评估基因表达和3C） 整合WES的发现，基因表达和组织免疫染色以定义 腺癌肺癌预记录。这项研究试图将方法转变为 通过发现可以利用在 在最早的阶段开发疫苗和适应性疗法以拦截疾病。冒险 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 预先记录。随着我们增加对疾病的分子发病机理和自然病史的了解， 发现关键的新垂体将促进疫苗的开发 侵入性肺癌。