(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

• 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
• 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

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，但对驱动免疫监视的肿瘤细胞源性危险信号知之甚少。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的复杂性。我们以前使用GEMM来确定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KrasG 12 D激活了涉及p19（Arf）和p53的遗传回路，促进了肿瘤的抑制和停止发展。相比之下，肺肿瘤通过表观遗传沉默p19（Arf）绕过这一遗传回路。在晚期肿瘤细胞中，p53下游的信号也触发NK和其他先天免疫细胞的阻滞和介导消除。KrasG 12 D阻滞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遗传改变并发展成肉瘤的机会。在本申请的目的1中，我们将直接研究先天免疫细胞在小鼠模型中检测和清除肿瘤前细胞的作用，其中控制致癌K-rasG 12 D的初始获得的事件独立于控制p53缺失的事件（从停滞状态释放所需的）。此外，我们将 测试NK细胞是否可以通过在这些病变中表达活化和抑制配体来增加和/或抑制清除。表达KrasG 12 D的p53缺陷肉瘤和肺腺癌的比较为研究肿瘤发生的早期事件如何决定抗肿瘤T细胞应答是否在体内具有保护性提供了一个强有力的平台。尽管肿瘤在相同的小鼠中发展，具有相同的起始遗传改变，表达相同的肿瘤抗原，并引发来自相同的初始T细胞群的应答，但表达抗原的肺腺癌在小鼠中发展，而表达抗原的肉瘤则没有。在目标2中，我们将比较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的转化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，以及危险信号的敲除是否可以帮助出现前的肿瘤破坏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的免疫原性更强。