Disrupting the immune and drug-privileged microenvironment in pancreas cancer

项目总结 胰腺导管腺癌(PDA)形成强烈的纤维炎症浸润物，有助于促进 疾病进展和治疗抵抗力。最近的进展已经确定了这方面的根本障碍 阻碍药物输送和抑制免疫力的复杂微环境。这些过程包括 由高浓度的透明质酸(HA)与水形成络合物而产生的令人望而却步的间质压力， 与纤维状胶原沉积相关的致密纤维化，以及多种免疫抑制和 促肿瘤细胞，如髓系抑制细胞和巨噬细胞。这支队伍聚集在这个 Project已经取得了上述许多开创性的发现。此外，我们还开发了几个 非常新颖和强大的实验平台，严格询问复杂的机制和 肿瘤微环境中不同隔室之间的相互作用共同促进 胰腺癌和转移瘤的存活率及治疗受阻。我们最重要的假设是 显著提高PDA患者的存活率将不仅需要靶向肿瘤上皮细胞，而且还需要 支持其发生的三个部分：造血细胞、间充质细胞和细胞外基质。在……里面 下面，我们建议研究细胞毒治疗与间质破坏和 髓系细胞调节，以最大限度地参与抗肿瘤免疫和治疗效果。我们会 在四个不同的实验平台中进行这些调查，这些平台提供互补的优势和 缓解限制：1)自体PDA的基因工程小鼠模型(GEMM)；2)同基因 同种异体移植；3)患者来源的异种移植(PDX)系统；以及4)患者来源的有机化合物(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).