An immune system biology approach to spatial and temporal mechanisms of cancer immunotherapy

项目摘要 胰腺癌（PDA）有望成为美国癌症相关死亡的第二大原因。 美国到2020年。人类PDA通常在肿瘤形成的后期发现，许多人难以接受。 一线治疗，5年生存率低（8%）。小鼠模型使PDA的研究更加深入 尽管这些模型经常不能概括人类PDA中的肿瘤异质性，但仍然是可行和准确的。 最近，宾夕法尼亚大学的Katelyn Byrne博士创建了一个肿瘤克隆文库， PDA自发小鼠模型。这些克隆涵盖了在免疫细胞中所见的免疫细胞异质性的谱。 人类PDA，使它们成为更好地了解这些肿瘤如何形成和对 免疫疗法重要的是，Byrne博士发现了T细胞浸润肿瘤克隆和T细胞浸润肿瘤克隆之间的二分法。 细胞排除肿瘤克隆对检查点阻断疗法的反应性，模拟人PDA 患者临床反应。免疫检查点阻断靶向负调节免疫途径 抑制效应子功能，恢复抗肿瘤免疫功能。令人惊讶的是，许多机械 检查点阻断的各个方面仍然没有得到很好的表征，可能是由于免疫细胞的多样性， 检查点阻断疗法可以起作用的人群和解剖位置。我相信我们的实验室 独特地定位以解决关于免疫细胞在免疫过程中的空间/解剖定位的问题。 检查站封锁，因为热尔曼实验室专门从事尖端的高分辨率显微技术。 我和伯恩博士建立了合作关系利用她的肿瘤克隆来研究 检查点阻断疗法的背后，特别是与治疗难治性肿瘤有关。我假设 肿瘤微环境中浸润免疫细胞亚群的时空分析， 在检查点阻断期间的肿瘤引流淋巴结将导致对 这些细胞的动态重编程和定位，这可能会揭示合理的新目标， 免疫力接近。在目标1中，我将确定检查点的功能解剖部位 阻断疗法与T细胞增殖、引发和定位有关。在目标2中，我将阐明 骨髓细胞影响肿瘤中T细胞包含/排斥表型的机制 微环境在目标3中，我将评估目标1和目标2的主要发现的可推广性， 更多的癌症模型，希望发现广泛适用的基本真理。 总之，这些研究将为驱动免疫抑制肿瘤的因素提供机制性见解。 微环境，影响治疗反应的因素，并有可能 翻译应用。在这个奖项下计划的活动将为我提供一个必要的培训 这将促进我作为一个独立研究人员的成长，并使我在一个 政府或学术机构都有我自己的实验室

PROJECT SUMMARY Pancreatic adenocarcinoma (PDA) is on track to be the second leading cause of cancer related deaths in the United States by 2020. Human PDA is often found at later stages of tumor formation, is refractory to many frontline therapies, and has a low (8%) 5-year survival rate. Mouse models have made research into PDA more feasible and accurate, though the models frequently fail to recapitulate the tumor heterogeneity in human PDA. Recently, Dr. Katelyn Byrne at the University of Pennsylvania generated a tumor clone library derived from the spontaneous mouse model of PDA. These clones cover the spectrum of immune cell heterogeneity seen in human PDA, making them a vital and powerful tool to better understand how these tumors form and respond to immunotherapies. Importantly, Dr. Byrne has found a dichotomy between T cell infiltrated tumor clones and T cell excluded tumor clones in their responsiveness to checkpoint blockade therapies, mimicking human PDA patient clinical responses. Immune checkpoint blockades target negative regulatory immune pathways constraining effector function, reinvigorating antitumor immunological functions. Surprisingly, many mechanistic aspects of checkpoint blockade remain poorly characterized, likely due to the variety of immune cell populations and anatomical locations at which checkpoint blockade therapies can act. I believe our lab will be uniquely situated to address questions concerning the spatial/anatomical localizations of immune cells during checkpoint blockade, since the Germain lab specializes in cutting-edge high resolution microscopic techniques. I have established a collaboration with Dr. Byrne to use her tumor clones to interrogate the mechanisms behind checkpoint blockade therapies, especially in relation to treatment-refractory tumors. I hypothesize that a spatio-temporal analysis of infiltrating immune cell subsets in the tumor microenvironment and tumor draining lymph node during checkpoint blockade will result in mechanistic insight into the dynamic reprogramming and localization of these cells, which could reveal novel targets for rational immunotherapeutic approaches. In Aim 1, I will determine the functional anatomic site(s) of checkpoint blockade therapy in relation to T cell proliferation, priming, and localization. In Aim 2, I will elucidate the mechanisms by which myeloid cells influence T cell inclusion/exclusion phenotypes in the tumor microenvironment. In Aim 3, I will evaluate the generalizability of my key findings from Aims 1 and 2 in additional cancer models, with the hope of discovering fundamental truths that are broadly applicable. Together, these studies will provide mechanistic insight into the factors driving immunosuppressive tumor microenvironments, the factors that influence therapeutic responsiveness, and has the potential for translational applications. The activities planned under this award will provide me with an essential training opportunity that will foster my growth as an independent researcher and position me for success at a government or academic institution with my own lab.