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: 10058759
• 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/10058759
• 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; Immunoprevention; 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; Occupational Exposure; Oils; Operative Surgical Procedures; Pathogenesis; Patients; Phase; Population; 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; agent orange; cancer invasiveness; clinically actionable; combustion product; cooking; disease natural history; exhaust; exome; high risk; imaging study; improved; nano-string; neoantigens; peripheral blood; premalignant; programmed cell death protein 1; 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.

非小细胞肺癌临床上可行的新抗原 肺癌是美国退伍军人癌症死亡的主要原因，也是世界上癌症死亡的主要原因 癌症死亡。退伍军人的环境暴露和烟草使用共同增加了风险。 释放针对肺癌前病变的免疫反应可能会改变治疗方法和结果。 在这里，我们建议为肺癌“拦截癌症”奠定基础，这一战略旨在阻止肺癌 癌前病变进展为浸润性癌症。在我们的初步研究中，我们已经开始评估 肺癌前病变的突变格局和相关的癌前微环境 外显子组 DNA 测序和免疫组织化学。值得注意的是，我们发现频繁的免疫效应细胞 浸润以及肺癌前病变免疫抑制的证据。这些发现引导我们 假设癌前相关新抗原 (PAN) 被识别并引发免疫反应 肺腺癌发展的最早点。这项研究将确定新表位 在侵袭性肺癌发生之前就进行靶向治疗，从而改变疾病拦截的方法 通过免疫预防和治疗疾病的最早阶段。 具体目标是： 1) 利用全外显子组 DNA 测序 (WES) 来确定计算定义的 原发肿瘤、癌前病变和邻近组织学正常肺的匹配组中的新抗原 组织。 2) 鉴定与肿瘤进展相关的功能相关新表位：T 的两个来源 细胞，一种来自 TIL，另一种来自外周血 PD1+ T 细胞，将用于识别新表位特异性 CD8+ T 细胞。为了提高筛查效率，我们将重点关注癌前患者之间共享的新抗原 可能与进展相关的病变和原发肿瘤。将进行功能测定 验证已识别的新表位。这将为未来的疫苗或过继细胞带来针对患者的新表位 非小细胞肺癌（NSCLC）的治疗。 3) 将免疫环境与 WES 定义的突变联系起来 我们将： 3A) 进行定量多重分析 前两个中使用的相同样本的免疫荧光染色旨在评估细胞的调节因子 介导的免疫并将其与癌前病变的突变景观和新表位联系起来 和肿瘤，3B) 利用包含 770 个免疫相关基因的 Nanostring 面板评估基因表达，3C) 整合 WES、基因表达和组织免疫染色的发现来定义 肺腺癌癌前病变。这项研究旨在改变方法 通过发现可用于预防和治疗肺腺癌的功能性新表位 开发疫苗和过继疗法以在最早阶段拦截疾病。随着来临 在筛查过程中，许多患者的影像学检查结果与局灶或多灶一致 癌前病变。随着我们对疾病的分子发病机制和自然史的了解不断增加， 关键新表位的发现将有助于为进展风险最高的人群开发疫苗 至浸润性肺癌。

项目成果

Lung Cancer and Immunity Markers.

• DOI: 10.1158/1055-9965.epi-20-0716
• 发表时间: 2020-12
• 期刊: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
• 作者: Lim RJ;Liu B;Krysan K;Dubinett SM
• 通讯作者: Dubinett SM