Studying factors controlling cancer progression and immune recognition in mouse models

研究小鼠模型中控制癌症进展和免疫识别的因素

• 批准号: 10707303
• 负责人: TYLER E. JACKS
• 金额: $ 93.49万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2029-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707303
• 关键词: Antigens; Area; CRISPR/Cas technology; Cancer Biology; Cancer Control; Cancer Model; Cancer Patient; Cancer Vaccines; Cells; Data Set; Development; Disease Progression; Dissociation; Evolution; Foundations; Functional disorder; Gene Expression; Genes; Genetic Engineering; Genetically Engineered Mouse; Human; Immune; Immune system; Immunotherapy; In Situ; Laboratories; Lung Adenocarcinoma; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Methods; Modeling; Molecular; Nature; Organoids; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Pre-Clinical Model; Preventative vaccination; Research; Specimen; System; T cell response; T-Cell Activation; T-Lymphocyte; Time; Vaccine Therapy; cancer cell; cancer type; cell type; clinical translation; experimental study; genetic profiling; genome editing; human model; improved; mouse model; novel; novel therapeutic intervention; response; single cell analysis; technology development; tool; transcriptomics; tumor; tumor microenvironment; tumor progression; vaccine strategy

Summary Over the past three decades, the Jacks laboratory has been a recognized leader in the development and characterization of genetically engineered mouse models of cancer, among other pre-clinical models. The laboratory has also studied human cancer specimens and datasets to validate finding from their experimental systems and to advance discoveries toward clinical translation. While Jacks laboratory has investigated many cancer types over time, this proposal is focused on models of lung adenocarcinoma and pancreatic ductal adenocarcinoma. By developing and deploying tools of genetic engineering and genetic profiling, such as CRISPR-based methods and single-cell analysis, the laboratory has pioneered new models and analytical approaches that have allowed for a deeper understanding of disease progression, including interactions between developing tumors and the immune system. This proposal builds on this foundation at the intersection of cancer biology and technology development to explore in detail the molecular and cellular aspects of tumor evolution. Single-cell profile methods will be augmented by spatial transcriptomics to characterize the changes in gene expression—in cancer cells as well as other cell types within the tumor microenvironment—in situ, rather than in dissociated cells. Genes and pathways implicated by this analysis will be subjected to functional analysis using organoid-based models as well as in the autochthonous setting. A second major theme of this proposal is the further exploration of tumor-immune interactions in lung cancer, which the laboratory has been studying for several years. Following up on experiments investigating the factors that control T cell activation and dysfunction in the setting of lung and pancreas cancer development, the laboratory will explore methods to provoke effective anti-tumor T cell responses as well as an improved response to immunotherapy. These studies will investigate the nature of the antigens and antigen combinations that induce effective T cell priming and activation, including through prophylactic and therapeutic vaccinations. Results of these experiments will inform new therapeutic approaches, including novel cancer vaccine strategies, in human cancer patients.

概括 在过去的三十年中，杰克实验室一直是该开发项目的公认领导者 癌症的一般工程小鼠模型以及其他临床前模型的表征。 该实验室还研究了人类癌症标本和数据集，以验证其发现 实验系统并推进临床翻译的发现。杰克实验室有 随着时间的流逝，该提案研究了许多癌症类型，重点是肺腺癌模型 和胰腺导管腺癌。通过开发和部署基因工程和 基因分析，例如基于CRISPR的方法和单细胞分析，实验室已经开创了 新的模型和分析方法，可以更深入地了解疾病 进展，包括发展肿瘤与免疫系统之间的相互作用。这个建议 建立在癌症生物学和技术发展的交集的基础上，以探索 详细说明肿瘤进化的分子和细胞方面。单细胞配置文件方法将得到增强 通过空间转录组学来表征基因表达的变化 - 在癌细胞以及 肿瘤微环境中的其他细胞类型 - 原位，而不是在解离细胞中。基因和 该分析实施的途径将使用基于器官的模型进行功能分析 以及在自我调节设置中。该提案的第二个主要主题是进一步的探索 实验室已经研究了几年的肺癌中肿瘤免疫相互作用。 跟进了调查控制T细胞激活和功能障碍的因素的实验 肺部和胰腺癌开发的设置，实验室将探索挑衅的方法 有效的抗肿瘤T细胞反应以及对免疫疗法的改善反应。这些研究 将研究影响有效T细胞启动的抗原和抗原组合的性质 和激活，包括通过预防性和治疗性疫苗接种。这些实验的结果 将告知人类癌症中新的治疗方法，包括新的癌症疫苗策略 患者。