Project 2

胰腺导管腺癌是一种极致命的疾病，其1年和5年生存率最低 任何癌症的发病率。这部分是由于胰腺癌细胞的极端转移行为， 他们对化学和放射疗法的极端抵抗力。重要的是，我们现在知道，一个强大的，但 然而，PDA中存在独特的纤维化和免疫抑制基质反应。这种强烈 纤维炎性反应或促结缔组织增生反应是PDA的主要特征， 抗肿瘤免疫细胞以及它们在肿瘤体积中移动和取样的能力。的确， 具有免疫检查点阻断或输注遗传修饰细胞的免疫疗法正在产生 在其他晚期恶性肿瘤中的临床反应显着，但迄今为止， 仅限于PDA。然而，集中的临床前策略破坏基质或特异性工程化T细胞， 治疗PDA的方法已显示出前景。因此，了解工程化T细胞的分子基础 浸润和鉴定策略以进一步增强它们在肿瘤块中的浸润，迁移， 癌症中的持久性和功能将为改善治疗的细胞工程策略提供信息。这里我们 使用综合实验，先进的成像和数学方法来测试一些重点假设。 建模以阐明体内和体外工程化平台中的工程化T细胞迁移机制 并利用基因组编辑和过表达来设计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， 细胞在整个肿瘤中移动，我们可以大大提高它们的功效， 靶向治疗和T细胞治疗，以改善疾病的结果。我们将剖析渗透机制， 工程化T细胞的寿命和功能，并确定工程化T细胞如何在细胞内迁移。 复杂的肿瘤环境。这些信息将被用来设计T细胞， 在整个肿瘤中移动。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细胞方法与合理的基质重建相结合。我们的目标与 项目1和3，我们寻求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.