(PQB3) Investigating innate immunosurveillance of oncogene-induced danger signals

(PQB3) 研究癌基因诱导的危险信号的先天免疫监视

基本信息

批准号：
8686200
负责人：
TYLER E. JACKS
金额：
$ 32.52万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-16 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8686200
关键词：
Affect American Antigens Automobile Driving Bypass Cancer Patient Cells Development Disease Disease Progression Early Diagnosis Epigenetic Process Event Genes Genetic Genetically Engineered Mouse Human Immune Immune response Immune system Immunologic Monitoring Immunotherapeutic agent In Vitro Intrinsic factor Lead Left Lesion Ligands Lung Adenocarcinoma Lung Neoplasms Malignant - descriptor Malignant Neoplasms Mediating Modeling Molecular Mouse Strains Mus Muscle Cells Mutagenesis Mutate Mutation Natural Killer Cells Neoplastic Muscle Cell Normal Cell Oncogenes Oncogenic Outcome Population Process Production Public Health Recruitment Activity Regulation Role Signal Transduction Staging Stream System T cell response T-Lymphocyte Testing Tissues Tumor Antigens Tumor Promotion Uncertainty Virus Diseases cell transformation cell type chemokine cost cytokine immune activation immune clearance immunogenic in vivo lung sarcoma metaplastic cell transformation mouse model neoplastic neoplastic cell novel prevent public health relevance research study response sarcoma senescence small hairpin RNA tumor tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Cancer immunosurveillance is a potential mechanism for immune recognition and elimination of pre-emergent tumor cells, but little is known about the tumor cell-derived danger signals that drive immunosurveillance. Genetically engineered mouse models (GEMMs) recapitulate cardinal features of human cancers, including interactions between tumor cells and their microenvironment, and have helped uncover complexities underlying tumor development. We have previously used GEMMs to identify similarities and differences between lung adenocarcinoma and sarcoma development. Expression of oncogenic KrasG12D by muscle cells activates a genetic circuit involving p19 (Arf) and p53 that promotes arrest and stops tumor development. By contrast, lung tumors bypass this genetic circuit by epigenetically silencing p19 (Arf). In advanced tumor cells, signals down-stream of p53 also trigger arrest and mediate elimination by NK and other innate immune cells. The fate of KrasG12D-arrested muscle cells is unclear, but immunosurveillance and elimination by innate immune cells could reduce the chances these pre-neoplastic cells acquire additional genetic alterations and develop into sarcomas. In Aim 1 of this application, we will directly investigate the role of innate immune cells in detecting and clearing pre-neoplastic cells in a mouse model in which the events controlling the initial acquisition of oncogenic K-rasG12D are independent of those controlling p53 deletion (required for release from an arrested state). Additionally, we will test whether NK cells can augment and/or inhibit clearance by expressing activating and inhibitory ligands in these lesions. The comparison of KrasG12D expressing p53-deficient sarcomas and lung adenocarcinomas provides a powerful platform for investigating how early events in tumorigenesis determine whether anti-tumor T cell responses are protective in vivo. Despite tumor development in identical mice, with identical initiating genetic alterations, expressing identical tumor antigens, and eliciting responses from identical populations of naive T cells, antigen-expressing lung adenocarcinomas develop in mice while antigen- expressing sarcomas do not. In Aim 2, we will compare early innate immune responses to sarcomas and lung adenocarcinomas and determine how environmental and cell-intrinsic responses to transformation contribute to innate activation and anti-tumor T cell responses. In Aim 3, we will identify the mechanisms by which immune cells become alerted to the presence of pre-neoplastic and fully transformed tumor cells and whether knockdown of danger signals can help pre-emergent tumors subvert immunosurveillance mechanisms and grow in vivo. These Aims will strengthen our understanding of the molecular and cellular events that regulate immunosurveillance at the earliest stages of malignant transformation and help us to understand why certain tumor types are more immunogenic as a result.

描述（由申请人提供）：癌症免疫监视是免疫识别和消除出现前肿瘤细胞的潜在机制，但对于驱动免疫监视的肿瘤细胞衍生的危险信号知之甚少。基因工程小鼠模型（GEMM）概括了人类癌症的主要特征，包括肿瘤细胞与其微环境之间的相互作用，并有助于揭示肿瘤发展背后的复杂性。我们之前曾使用 GEMM 来识别肺腺癌和肉瘤发展之间的相似性和差异。肌肉细胞表达致癌性 KrasG12D 会激活涉及 p19 (Arf) 和 p53 的遗传回路，从而促进肿瘤停滞并阻止肿瘤发展。相比之下，肺部肿瘤通过表观遗传沉默 p19 (Arf) 来绕过这个遗传回路。在晚期肿瘤细胞中，p53 下游的信号也会触发 NK 和其他先天免疫细胞的停滞并介导消除。 KrasG12D 抑制的肌肉细胞的命运尚不清楚，但先天免疫细胞的免疫监视和消除可以减少这些肿瘤前细胞获得额外基因改变并发展成肉瘤的机会。在本申请的目标 1 中，我们将直接研究先天免疫细胞在检测和清除小鼠模型中的肿瘤前细胞中的作用，其中控制致癌 K-rasG12D 初始获得的事件独立于控制 p53 删除的事件（从被捕状态释放所需的）。此外，我们将测试 NK 细胞是否可以通过在这些病变中表达激活和抑制配体来增强和/或抑制清除。表达 p53 缺陷的肉瘤和肺腺癌的 KrasG12D 的比较为研究肿瘤发生的早期事件如何确定抗肿瘤 T 细胞反应在体内是否具有保护性提供了一个强大的平台。尽管肿瘤在相同的小鼠中发生，具有相同的起始遗传改变，表达相同的肿瘤抗原，并引发相同的初始T细胞群的反应，但表达抗原的肺腺癌在小鼠中发生，而表达抗原的肉瘤则不然。在目标 2 中，我们将比较对肉瘤和肺腺癌的早期先天免疫反应，并确定环境和细胞内在对转化的反应如何促进先天激活和抗肿瘤 T 细胞反应。在目标 3 中，我们将确定免疫细胞对肿瘤前和完全转化的肿瘤细胞的存在发出警报的机制，以及危险信号的敲低是否可以帮助出现前的肿瘤颠覆免疫监视机制并在体内生长。这些目标将加强我们对在恶性转化的最早阶段调节免疫监视的分子和细胞事件的理解，并帮助我们理解为什么某些肿瘤类型因此更具免疫原性。