Autologous Humanized Mouse Model of Non-Small Cell Lung Cancer (NSCLC) to Investigate the Tumor-Immune Landscape and Its Response to Treatment

项目总结 非小细胞肺癌(NSCLC)仍然是全球癌症死亡的主要原因，尽管 以免疫为基础的疗法取得了令人兴奋的进展。这些疗法虽然对一些患者非常有效， 对大多数非小细胞肺癌患者无效。治疗失败的原因仍然不完全清楚， 正如局部肿瘤微环境(TME)在影响肿瘤生长中的作用一样，在存在和 缺乏这些治疗方法。 为了更好地研究人类肿瘤免疫相互作用和免疫疗法，我们开发了一种人源化的 支持携带匹配的人类造血系统和肿瘤的小鼠植入的小鼠模型 来自一名非小细胞肺癌患者。此外，该模型在支持功能性髓系细胞方面是独一无二的。 先天免疫系统的一部分。我们建议使用这些自体植入的人源化非小细胞肺癌PDX 应用流式细胞术、免疫染色和单细胞基因组分析详细研究TME的模型 以确定存在的细胞的转录和蛋白质组状态。我们将把肿瘤的生长与 用这些方法鉴定了特定的细胞群体，增强了我们对活跃在 肿瘤对血液驻留的免疫细胞，识别已建立的和可能的新的免疫网络 TME的功能障碍。有了这些知识，我们将探索这些患者模型中活跃的通路 使用我们确定的针对免疫衰竭和肿瘤促进机制的特定药物。我们的目标是获得 更深入地了解TME和免疫疗法是如何相互作用的，并开发这些免疫替身 小鼠作为模型，可以预测患者对特定免疫疗法的反应。 首席研究员是一名内科科学家，拥有遗传学博士学位，博士后和临床培训。 医学肿瘤学。他的职业目标是成为一名研究肿瘤免疫的独立研究员 互动。拟议的K08培训计划将为应聘者提供指导和课程建设 执行拟议项目并在翻译领域取得独立所需的专业知识 免疫肿瘤学。

PROJECT SUMMARY Non-small cell lung cancer (NSCLC) remains the major cause of cancer mortality across the globe, despite exciting advances in immune-based therapies. These therapies, while dramatically effective in some patients, are ineffective in the majority of NSCLC patients. The causes of treatment failure remain incompletely understood, as is the role of the local tumor microenvironment (TME) in influencing tumor growth, both in the presence and absence of these therapies. To better study human tumor-immune interactions and immunotherapeutics, we have developed a humanized mouse model that supports the engraftment of mice bearing a matched human hematopoietic system and tumor from an individual NSCLC patient. In addition, this model is unique in its support of functional myeloid cells as part of the innate immune system. We propose to use these autologously-engrafted humanized NSCLC PDX models to study the TME in detail, employing flow cytometric, immunostaining and single cell genomic analyses to characterize the transcriptional and proteomic states of the cells present. We will correlate tumor growth to specific cell populations identified with these methods, enhancing our understanding of the pathways active in tumor- vs blood-resident immune cells, and identifying established and possibly new networks of immune dysfunction in the TME. Armed with this knowledge, we will probe the pathways active in these patient models using drugs specific to the immune exhaustion and tumor promoting mechanisms we identify. Our goal is to gain a deeper understanding of how the TME and immunotherapeutics interact, and to develop these immune avatar mice as models that may predict a patient’s response to a particular immunotherapy. The principal investigator is a physician-scientist, with a PhD in genetics and post-doctoral and clinical training in Medical Oncology. His career goal is to become an independent investigator studying tumor-immune interactions. The proposed K08 training plan will provide the candidate with mentorship and coursework to build the expertise necessary to execute the proposed project and become independent in the field of translational immuno-oncology.