Project 2

胰腺导管腺癌是一种极其致命的疾病，其1年和5年生存率最低。 任何癌症的比率。这在一定程度上是由于胰腺癌细胞的极端转移行为和 他们对化学疗法和放射疗法都有极端的抵抗力。重要的是，我们现在知道，一个强大的，但 然而，PDA存在独特的、纤维化的和免疫抑制的间质反应。如此激烈 纤维炎性或促结缔组织增生性反应本质上是PDA的病因学反应，并限制了 抗肿瘤免疫细胞以及它们在整个肿瘤体积中移动和取样的能力。的确， 免疫检查点阻断或转基因细胞输注的免疫疗法正在产生 在其他晚期恶性肿瘤中有显著的临床反应，但到目前为止，成功的更多 仅限于掌上电脑。然而，专注于临床前策略来破坏基质或专门设计T细胞 治疗方法在PDA方面显示出了希望。因此，了解工程T细胞的分子基础 并确定进一步加强其在肿瘤肿块中的渗透、迁移的策略， 癌症中的持久性和功能将为改进治疗的细胞工程策略提供信息。在这里，我们 使用集成实验、高级成像和数学方法测试多个聚焦假设 在体内和体外工程平台中阐明工程T细胞迁移机制的建模 并利用基因组编辑和过度表达来设计能够最大限度地渗透和移动的T细胞 在复杂的肿瘤微环境中。我们假设，通过增强工程T细胞的能力 细胞在肿瘤中移动，我们可以深刻地提高它们的效率，并使用基质的组合 靶向治疗和T细胞治疗以改善疾病结局。我们将剖析渗透的机制， 工程T细胞的寿命和功能，并决定工程T细胞如何在体内迁移 物理上复杂的肿瘤环境。这些信息将最有效地用于工程T细胞 在整个肿块中移动。使用这些细胞，我们将进行严格的临床前评估 我们的工程化T细胞方法与Rational间质再工程相一致。我们的目标与 项目1和项目3，我们试图共同阐明免疫细胞迁移的基本机制 并创新新的细胞工程方法来根除癌症。

Pancreatic ductal adenocarcinoma is an extremely lethal disease with the lowest 1-year and 5-year survival rates of any cancer. This is due, in part, to the extremely metastatic behavior of pancreas carcinoma cells and their extreme resistance to both chemical and radiotherapies. Importantly, we now know that a strong, but nevertheless unique, fibrotic and immunosuppressive stromal response is present in PDA. This intense fibroinflammatory, or desmoplastic, response is essentially pathognomonic for PDA and limits infiltration of anti-tumor immune cells and also their ability to move throughout and sample the tumor volume. Indeed, immunotherapies with immune checkpoint blockade or infusion of genetically modified cells are producing remarkable clinical responses in other advanced malignancies, but to date, success has been much more limited in PDA. However, focused preclinical strategies to disrupt the stroma or specifically engineer T cell therapies have shown promise in PDA. Thus, understanding the molecular basis for engineered T cell infiltration and identifying strategies to further enhance their infiltration, migration throughout tumor masses, and persistence and function in cancer will inform cell engineering strategies for improved treatment. Here, we test a number of focused hypotheses using integrated experiments, advanced imaging, and mathematical modeling to elucidate engineered T cell migratory mechanisms both in vivo and in engineered platforms in vitro and utilize genome editing and overexpression to engineer T cells that can maximally infiltrate and move throughout complex tumor microenvironments. We hypothesize that by enhancing the ability of engineered T cells to move throughout tumor we can profoundly improve their efficacy and employ combinations of stroma targeting and T cell therapies to improve disease outcomes. We will dissect mechanisms governing infiltration, longevity and functionality of engineered T cells and determine how engineered T cell migrate within the physically complex tumor environments. This information will be used engineer T cells that most effectively move throughout the entire tumor mass. Using these cells, we will perform rigorous preclinical evaluation of our engineered T cell approach in concert with rational stroma re-engineering. Our goals are aligned with Projects 1 and 3 where we seek to collectively elucidate fundamental mechanisms of immune cell migration and to innovate novel cell engineering approaches to eradicate cancer.