Targeting the fibroblast-immune cell crosstalk to relieve immune suppression in the pancreatic cancer microenvironment

靶向成纤维细胞-免疫细胞串扰以缓解胰腺癌微环境中的免疫抑制

基本信息

批准号：
10535373
负责人：
Marina Pasca Di Magliano
金额：
$ 56.42万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10535373
关键词：
Ablation Acylation Address Adult Affect Animals Binding CD4 Positive T Lymphocytes Cell Communication Cell Compartmentation Cells Characteristics Coculture Techniques Data Disease Disease Progression Disease model Embryo Enzymes Epithelial Epithelial Cells Family Fibroblasts Gene Expression Genes Genetically Engineered Mouse Goals Grant Growth Human Immune Immunization Immunosuppression Immunotherapy KRAS oncogenesis KRAS2 gene Lesion Ligands MAP Kinase Gene MEKs Maintenance Malignant - descriptor Malignant Neoplasms Malignant neoplasm of pancreas Maps Mediating Mediator of activation protein Membrane Mus Mutation Neoplasm Transplantation Non-Malignant Oncogenic Organoids Pancreas Pancreas Transplantation Pancreatic Intraepithelial Neoplasia Pathway interactions Pharmacology Phenotype Porcupines Proteins Reaction Regulation Resistance Role Sampling Shapes Signal Pathway Signal Transduction Source System T cell differentiation T-Cell Activation T-Lymphocyte TCF Transcription Factor Testing Tumor Immunity Tumor Suppressor Proteins Tumor-infiltrating immune cells Up-Regulation WNT Signaling Pathway activating transcription factor advanced disease base carcinogenesis cell type chemotherapy design human RNA sequencing immune checkpoint blockade immunoregulation inhibitor neoplastic cell novel novel therapeutic intervention pancreatic cancer cells pancreatic cancer model pancreatic cancer patients pancreatic tumorigenesis prevent receptor recombinase single-cell RNA sequencing transcription factor tumor tumor microenvironment tumor-immune system interactions

项目摘要

ABSTRACT Pancreatic cancer is characterized by an extensive fibroinflammatory reaction, or tumor stroma. While immune cells are abundant within the stroma, they are largely immune suppressive, and therefore pancreatic cancer is largely unresponsive to immunotherapy. Genetically engineered mouse models of pancreatic cancer recapitulate the stepwise progression of pancreatic cancer, and are ideal to study precursor lesions, such as pancreatic intraepithelial neoplasia (PanIN). Analysis of the immune infiltrates at the PanIN stage revealed that immune suppression is established very early on and precedes malignant progression. The mechanisms underlying the establishment of the immune suppression in pancreatic cancer remain unknown and understanding them is of fundamental importance to design new chemotherapy approaches for pancreatic cancer. We previously used single cell RNA sequencing to characterize gene expression profiles in the human pancreatic cancer immune infiltrate. We then mapped potential cell-cell interactions within the microenvironment based on reciprocal expression of ligands and receptors. Among predicted interactions, we identified WNT signaling activation in the T cell compartment of pancreatic cancer, driven by ligands expressed by tumor cells and cancer associated fibroblasts (CAFs). We and others have previously associated inappropriate activation of embryonic signaling pathways, including WNT signaling, as a characteristic of pancreatic cancer. WNT signaling is one of the core pathways activated in pancreatic cancer. We previously showed that ablation of epithelial WNT signaling inhibits the onset of pancreatic carcinogenesis, but the potential role of WNT in the pancreatic cancer microenvironment and specifically in immune cells is unknown. CAFs express several ligands of the WNT family; to ablate their expression, we inactivated PORCN (PORCUPINE), a transmembrane enzyme required for acylation and secretion of WNT ligands, in pancreatic fibroblasts. We then transplanted pancreatic cancer cells and observed reduced growth. To determine whether T cell activation of WNT signaling was important for this effect, we generated mice where the transcription factors TCF7, encoding for the protein TCF1, was inactivated in CD4+ T cells. In these animals, we observed reduced growth of transplanted tumors, alterations in the CAF phenotype, and increased activation of anti-tumor immunity. In this proposal, we plan to build on our preliminary data to dissect the mechanism of WNT signaling driven immune suppression in pancreatic cancer. The long term goal is to design targeting approaches that might reverse immune suppression in this disease.

抽象的胰腺癌的特征是广泛的肌瘤反应或肿瘤基质。同时免疫细胞在基质内丰富，它们在很大程度上是免疫抑制性的，因此胰腺癌是对免疫疗法的反应很大。胰腺癌的基因工程小鼠模型概括胰腺癌的逐步进展，是研究前体病变的理想选择，例如胰腺上皮内肿瘤（Panin）。对Panin阶段的免疫浸润物的分析表明，免疫抑制是在很早就建立的，并且先于恶性进展。机制胰腺癌中建立免疫抑制的基础仍然未知，并且理解它们对于设计新的化学疗法方法至关重要癌症。我们先前使用单细胞RNA测序来表征人类的基因表达谱胰腺癌免疫浸润。然后，我们在微环境中绘制了潜在的细胞 - 细胞相互作用基于配体和受体的相互表达。在预测的互动中，我们确定了Wnt 由肿瘤细胞表达的配体驱动的胰腺癌T细胞室中的信号传导激活和癌症相关的成纤维细胞（CAF）。我们和其他人以前具有不适当的激活胚胎信号通路（包括Wnt信号传导）是胰腺癌的特征。 wnt信号传导是胰腺癌激活的核心途径之一。我们先前表明上皮wnt的消融信号传导抑制胰腺癌发生的发作，但WNT在胰腺癌中的潜在作用微环境，特别是在免疫细胞中的环境尚不清楚。咖啡馆表达了Wnt家族的几个配体；为了消灭它们的表达，我们灭活了猪（豪猪），这是一种跨膜酶胰腺成纤维细胞中Wnt配体的酰化和分泌。然后我们移植胰腺癌细胞并观察到降低的生长。确定Wnt信号的T细胞激活是否对此很重要效果，我们生成了小鼠，其中转录因子TCF7（编码蛋白质TCF1）被灭活在CD4+ T细胞中。在这些动物中，我们观察到移植肿瘤的生长减少，CAF改变了表型和抗肿瘤免疫的激活增加。在此提案中，我们计划以初步为基础剖析Wnt信号传导驱动免疫抑制在胰腺癌中的数据。长期目标是设计可能在该疾病中逆转免疫抑制的靶向方法。