Disrupting the immune and drug-privileged microenvironment in pancreas cancer

项目摘要 胰腺导管腺癌（PDA）发生强烈的纤维炎性浸润，有助于促进 疾病进展和治疗抗性。最近的进展确定了这方面的主要障碍， 复杂的微环境，阻碍药物输送和抑制免疫力。这些过程包括 由高浓度的透明质酸（HA）与水复合产生的抑制性间隙压力， 与纤维状胶原沉积相关的致密纤维化，以及多种类型的免疫抑制和 促肿瘤发生细胞，如骨髓来源的抑制细胞和巨噬细胞。这个团队聚集在这个 该项目取得了上述许多开创性的发现。此外，我们还开发了多个 高度新颖和强大的实验平台，以严格询问复杂的机制， 肿瘤微环境中各种区室之间的相互作用共同促进了 胰腺癌和转移的存活率并阻碍治疗。我们的首要假设是 显著提高PDA患者的存活率不仅需要靶向肿瘤上皮细胞， 支持其肿瘤发生的三个区室：造血、间充质和细胞外基质。在 下面，我们建议研究细胞毒疗法与基质破坏的组合， 骨髓细胞调节以最大化抗肿瘤免疫和治疗功效的参与。我们将 在四个不同的实验平台上进行这些研究，这些平台提供互补的优势， 缓解局限性：1）本地PDA的基因工程小鼠模型（GEMM）; 2）同系 同种异体移植物; 3）患者来源的异种移植物（PDX）系统;和4）患者来源的类器官（PDO）。

PROJECT SUMMARY Pancreatic ductal adenocarcinomas (PDA) develop an intense fibroinflammatory infiltrate that helps promote disease progression and therapeutic resistance. Recent progress has identified essential barriers in this complex microenvironment that impede drug delivery and suppress immunity. These processes include the prohibitive interstitial pressures generated by high concentrations of hyaluronan (HA) complexed with water, dense fibrosis associated with fibrillar collagen deposition, and multiple classes of immunosuppressive and pro-tumorigenic cells such as myeloid-derived suppressor cells and macrophages. The team assembled in this project has made many of the seminal discoveries described above. In addition, we have developed several highly novel and powerful experimental platforms to rigorously interrogate the complex mechanisms and interactions among various compartments in the tumor microenvironment that collectively conspire to promote the survival of pancreas cancers and metastases and thwart treatment. Our overarching hypothesis is that significantly improving survival for PDA patients will require targeting not only the tumor epithelial cell, but also the three compartments that support its oncogenesis: hematopoietic, mesenchymal and extracellular matrix. In the following, we propose to investigate the combination of cytotoxic therapy with stromal disruption and myeloid cell modulations to maximize engagement of anti-tumor immunity and treatment efficacy. We will pursue these investigations in four distinct experimental platforms that offer complementary strengths and mitigate limitations: 1) genetically engineered mouse models (GEMM) of autochthonous PDA; 2) syngeneic allografts; 3) patient-derived xenograft (PDX) systems; and 4) patient-derived organoids (PDO).