Establishment and regulation of the immune suppressive microenvironment in pancreatic cancer

胰腺癌的特点是广泛的免疫抑制纤维炎症间质。这个 对这种纤维炎症反应的调节仍不完全清楚。因此，试图将 基质在临床试验中基本上没有成功。此外，免疫疗法只使一小部分人受益。 胰腺癌患者，因为我们还不完全了解这种免疫抑制的机制 疾病，因此无法逆转。这项提议的目标是为我们的根本利益做出贡献 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髓系细胞，这是微环境的丰富组成部分。我们的预赛 数据显示，由于致癌基因Kras在肿瘤或癌细胞中的表达，成纤维细胞 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/STAT3信号和癌细胞来源的代谢物联合介导成纤维细胞重编程 在细胞培养条件下最低。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、小鼠和人类系统相结合的不同致癌阶段(目的 1)。进一步，我们将研究成纤维细胞重编程在介导 抑制性免疫微环境(目标2)。最后，我们将探索对成纤维细胞重新编程的方法 预防或逆转致癌作用(目标3)。总之，提出的实验将阐明功能 调控胰腺癌微环境，并有可能找出新的靶向 微环境作为联合治疗的一个组成部分。

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.