Developing translationally-relevant genetically engineered mouse models of lung adenocarcinoma for investigations in cancer immunology

开发与翻译相关的肺腺癌基因工程小鼠模型，用于癌症免疫学研究

基本信息

批准号：
10608078
负责人：
Nikhil Joshi
金额：
$ 54.66万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10608078
关键词：
Address Alleles Animal Model Antibodies Antigens Antitumor Response Benzo(a)pyrene CD4 Positive T Lymphocytes CD8B1 gene Cancer Biology Cancer Model Cancer Patient Cell Communication Cell Line Cell Transplantation Cells Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Cytometry Data Desmoplastic Development Diagnosis Disease Disseminated Malignant Neoplasm Engineering Generations Genetically Engineered Mouse Growth Histologic Histology Human Human Biology Immune Immune Tolerance Immune checkpoint inhibitor Immune response Immunotherapeutic agent Immunotherapy Infection Inflammation Investigation KPC model Lentivirus Ligands Lung Adenocarcinoma Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Mediating Modeling Mus Mutagens Mutate Mutation Myelogenous Neoplasm Metastasis Organoids PD-1/PD-L1 PDL1 pathway Pancreas Pancreatic Ductal Adenocarcinoma Patients Regulatory T-Lymphocyte Research Research Personnel Role STK11 gene Scientist Shapes Standardization T cell infiltration T cell response T-Lymphocyte TP53 gene Testing Time Tobacco Translational Research Transplantation Treatment Efficacy Tumor-infiltrating immune cells Work anti-cancer anti-tumor immune response cancer type drug testing fighting human disease immune cell infiltrate immunogenic improved interest lung development lung sarcoma neoantigens novel pancreatic ductal adenocarcinoma model pancreatic neoplasm patient response programmed cell death ligand 1 programmed cell death protein 1 response single-cell RNA sequencing success therapy resistant tool transcriptomics translational potential treatment response tumor tumor growth tumor immunology tumor microenvironment tumor progression tumor-immune system interactions

项目摘要

Immune checkpoint inhibitors (ICIs) are extending the survival of patients with advanced, metastatic cancer, across many cancer types. Remarkably, immunotherapies may be curative, yet, only a fraction of cancer pa- tients have strong durable responses to ICIs. Response rates also differ greatly between cancer types, and some ICIs are only effective against a handful of cancers. The reasons for this remain unclear, underscoring the need for further research. Many ICIs, like antibodies targeting the PD-1/PD-L1 pathway, act on tumor-specific T cells that are already fighting the cancer at the time the patient is diagnosed with disease. The therapies reinvigorate T cells and cause them to attack and sometimes destroy the cancer. Little is known about the T cells that mediate thera- peutic responses or the factors that modulate their therapeutic efficacy. Thus, there is great interest in deter- mining how these therapies work and in augmenting them so that response rates increase. Unfortunately, it has not been easy, because few animal models recapitulate the natural biology of human cancer and elicit de- tectable anti-tumor immune responses. Genetically engineered mouse (GEM) models are widely used for stud- ies in cancer biology because they allow investigators to study developing tumors and to understand how tu- mors change over the course of disease. Yet, these gold-standard models are not used for cancer immunology studies because tumors do not express neoantigens, which are required for anti-tumor T cell responses. It has been challenging to develop GEM models where tumors express neoantigens. To remedy this problem, we engineered the “NINJA” mouse, and, in this proposal, we will use NINJA to generate “immunogenic” GEM models for cancer (i.e., models that elicit anti-cancer immune responses). We will standardize immunogenic models for lung and pancreatic cancer, investigate how neoantigens alter the immune cell infiltrates into tu- mors, and confirm their translational potential as faithful mimics of human cancer. Moreover, we will develop cell line and organoid models from these immunogenic GEMs, which will greatly increase the available tools for researchers in lung and pancreatic cancer. These state-of-the-art models will allow scientists to look at lung and pancreatic tumors at early stages (before cancers would be diagnosed in a patient), and to figure out how these early tumors and immune cells interact. Moreover, our studies will validate NINJA as a platform that can be used by other investigators for the genera- tion of immunogenic GEMs for other cancer types. As these models can be used to improve responses of pa- tients to immunotherapy, NINJA will be useful for enhancing the applicability of almost any GEM model for translational research.

免疫检查点抑制剂（ICI）正在延长晚期转移性癌症患者的存活，在许多癌症类型中。值得注意的是，免疫疗法可能是治愈性的，但只有一小部分癌症对ICIS的耐久响应良好。癌症类型之间的回应率也有所不同，并且有些ICI仅对少数癌症有效。此原因尚不清楚，强调需要进一步研究。许多ICI，例如针对PD-1/PD-L1途径的抗体，作用于已经已经存在的肿瘤特异性T细胞当患者被诊断出患有疾病时，与癌症作斗争。疗法振兴了T细胞和导致他们攻击，有时破坏癌症。关于介导thera-的T细胞知之甚少分类或调节其治疗效率的因素。这是对确定的极大兴趣 - 挖掘这些疗法的工作原理并增强它们，以提高回应率。不幸的是，它并不容易，因为很少有动物模型概括了人类癌症的自然生物学，并引起了人们的影响可探测的抗肿瘤免疫反应。基因工程的小鼠（GEM）模型被广泛用于螺柱 IES癌症生物学中的IE是因为它们允许研究人员研究发展肿瘤，并了解如何在整个疾病过程中，莫尔斯发生了变化。但是，这些金色标准模型不用于癌症免疫学研究是因为肿瘤不表达抗肿瘤T细胞反应所需的新抗原。开发肿瘤表达新抗原的宝石模型的挑战。为了解决这个问题，我们设计了“忍者”鼠标，在此提案中，我们将使用忍者生成“免疫原性”宝石癌症模型（即引发抗癌免疫调查的模型）。我们将标准化免疫原性肺癌和胰腺癌的模型，研究新抗原如何改变免疫细胞浸润到Tu- MORS，并确认其转化潜力是人类癌症的忠实模仿。而且，我们将发展这些免疫原性宝石的细胞系和类器官模型将大大增加可用工具肺癌和胰腺癌研究人员。这些最先进的模型将使科学家在早期阶段查看肺和胰腺肿瘤（之前癌症将在患者中诊断出来），并弄清楚这些早期肿瘤和免疫细胞如何相互作用。此外，我们的研究将验证忍者作为一个平台，其他研究人员可以将其用于属用于其他癌症类型的免疫原性宝石。由于这些模型可用于改善PA-的响应免疫疗法的特征，忍者将有助于增强几乎所有宝石模型的适用性翻译研究。