Studying factors controlling cancer progression and immune recognition in mouse models

摘要 在过去的三十年里，杰克斯实验室一直是公认的开发和 在其他临床前模型中，对癌症的基因工程小鼠模型进行表征。 该实验室还研究了人类癌症样本和数据集，以验证从他们的 实验系统，并将发现推进到临床翻译。而杰克斯实验室有 随着时间的推移，研究了许多癌症类型，这项建议集中在肺腺癌的模型上 和胰腺导管腺癌。通过开发和部署基因工程工具和 基因图谱，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，包括发展中的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在这个基础上来探索 详述肿瘤进化的分子和细胞方面。单细胞剖面法将得到增强 通过空间转录切割来表征基因表达的变化-在癌细胞中以及 肿瘤微环境中的其他细胞类型--原位，而不是在分离的细胞中。基因和 这一分析所涉及的通路将使用基于有机物的模型进行功能分析 以及在原生环境中。这项建议的第二个主要主题是进一步探索 关于肺癌中肿瘤-免疫相互作用的研究，该实验室已经研究了几年。 控制T细胞活化和功能障碍因素的实验研究进展 根据肺癌和胰腺癌的发展情况，实验室将探索激发方法 有效的抗肿瘤T细胞反应以及对免疫治疗的改善反应。这些研究 将研究诱导有效的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 将为人类癌症提供新的治疗方法，包括新的癌症疫苗策略 病人。

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.