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性间质。这个

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.