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

描述（由申请人提供）：癌症免疫监视是免疫识别和消除肿瘤细胞的潜在机制，但对驱动免疫监视的肿瘤细胞来源的危险信号知之甚少。基因工程小鼠模型（GEMMs）概括了人类癌症的基本特征，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。我们之前已经使用gem来识别肺腺癌和肉瘤发展之间的异同。肌肉细胞表达的致癌KrasG12D激活了一个涉及p19 （Arf）和p53的遗传回路，促进阻止和阻止肿瘤的发展。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。krasg12d阻滞肌肉细胞的命运尚不清楚，但免疫监视和先天免疫细胞的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，我们将在小鼠模型中直接研究先天免疫细胞在检测和清除肿瘤前细胞中的作用，在小鼠模型中，控制致癌K-rasG12D初始获取的事件独立于控制p53缺失的事件（从捕获状态释放所必需的）。此外，我们将

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.