Studying factors controlling cancer progression and immune recognition in mouse models

总结 在过去的三十年里，杰克实验室一直是公认的领导者， 在其他临床前模型中，基因工程小鼠癌症模型的表征。 该实验室还研究了人类癌症标本和数据集，以验证他们的发现。 实验系统和推进临床转化的发现。虽然Jacks实验室 随着时间的推移，研究了许多癌症类型，该提案侧重于肺腺癌模型 和胰腺导管腺癌。通过开发和部署基因工程工具， 基因分析，如基于CRISPR的方法和单细胞分析，该实验室开创了 新的模型和分析方法，使人们能够更深入地了解疾病 进展，包括发展肿瘤和免疫系统之间的相互作用。这项建议 在癌症生物学和技术发展的交叉点上建立这个基础， 详细介绍了肿瘤演变的分子和细胞方面。单细胞分析方法将得到加强 通过空间转录组学来表征癌细胞中基因表达的变化， 肿瘤微环境中的其他细胞类型-原位，而不是解离细胞。基因和 该分析所涉及的途径将使用基于类器官的模型进行功能分析 以及在本土的设置。本提案的第二个主题是进一步探讨 肺癌的肿瘤免疫相互作用，实验室已经研究了好几年。 对研究控制T细胞活化和功能障碍的因素的实验进行了跟踪， 设置肺癌和胰腺癌的发展，实验室将探索方法，以挑起 有效的抗肿瘤T细胞应答以及对免疫疗法的改善的应答。这些研究 将研究诱导有效T细胞引发的抗原和抗原组合的性质 和活化，包括通过预防性和治疗性疫苗接种。这些实验结果 将为人类癌症的新治疗方法提供信息，包括新的癌症疫苗策略， 患者

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.