Establishment and regulation of the immune suppressive microenvironment in pancreatic cancer

胰腺癌的特征是广泛的免疫抑制性纤维炎性间质。的 这种纤维炎性反应的调节仍然不完全清楚。因此，试图针对 基质在临床试验中大部分是不成功的。此外，免疫疗法仅使少数患者受益。 胰腺癌患者，因为我们不完全了解免疫抑制的机制， 疾病，因此无法逆转。该提案的目标是促进我们的基本 了解胰腺癌微环境的建立、调节和功能作用。 我们将重点关注成纤维细胞和骨髓细胞，微环境的丰富成分。我们的初步 数据显示，在肿瘤或癌细胞中，成纤维细胞响应致癌Kras表达， 重新编程并激活炎症基因表达谱。此外，我们的初步数据显示， JAK/Stat 3信号传导和癌细胞衍生代谢物的组合介导成纤维细胞重编程， 至少在细胞培养条件下。在这里，我们建议研究成纤维细胞重编程的机制， 使用体内和体外、小鼠和人类系统的组合来研究癌发生的不同阶段（Aim 1）。此外，我们将研究成纤维细胞重编程在介导细胞凋亡中的作用。 抑制性免疫微环境（Aim 2）。最后，我们将探索重新编程成纤维细胞的方法， 预防或逆转致癌作用（目标3）。总之，提出的实验将阐明功能性 调节胰腺癌微环境，并可能确定新的方法来靶向 微环境作为联合治疗的组成部分。

Pancreatic cancer is characterized by an extensive immunosuppressive fibroinflammatory stroma. The regulation of this fibroinflammatory reaction remains incompletely understood. As a result, attempts to target the stroma in clinical trials have been largely unsuccessful. Further, immunotherapy only benefits a small number of pancreatic cancer patients, as we do not fully understand the mechanisms of immune suppression in this disease, and are thus unable to reverse them. The goal of this proposal is to contribute to our fundamental understanding of the establishment, regulation and functional role of the pancreatic cancer microenvironment. We will focus on fibroblasts and myeloid cells, abundant components of the microenvironment. Our preliminary data show that, in response to oncogenic Kras expression in neoplastic or cancer cells, fibroblasts are reprogrammed, and activate an inflammatory gene expression profile. Further, our preliminary data show that a combination of JAK/Stat3 signaling and cancer-cell derived metabolites mediates fibroblast reprogramming, at least in cell culture conditions. Here, we propose to investigate the mechanism of fibroblast reprogramming at different stages of carcinogenesis using a combination of in vivo and in vitro, mouse and human systems (Aim 1). Further, we will investigate the effect of fibroblast reprogramming in mediating the establishment of the suppressive immune microenvironment (Aim 2). Finally, we will explore modalities to reprogram fibroblasts to prevent or reverse carcinogenesis (Aim 3). Together, the experiments proposed will shed light on the functional regulation of the pancreatic cancer microenvironment, and potentially identify new approaches to target the microenvironment as a component of combination therapy.