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Interrupting Cellular Crosstalk in the Immunosuppressive Microenvironment of Pancreas Cancer

中断胰腺癌免疫抑制微环境中的细胞串扰

基本信息

批准号：
10242453
负责人：
Howard C Crawford
金额：
$ 52.8万
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：
2017
资助国家：
美国
起止时间：
2017-09-30 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10242453
关键词：
Ablation Adenocarcinoma Cell Affect Animal Model Antigen-Antibody Complex Arginine Biocompatible Materials Biological Models Biology CD8-Positive T-Lymphocytes Cancer Patient Cell Communication Cells Communication Complex DTR gene Engineering Environment Epidermal Growth Factor Receptor Epithelial Epithelium Feedback Fibroblasts Genetically Engineered Mouse Goals Growth Factor Human IL6 gene Immune Immune checkpoint inhibitor Immune response Immune system Immunosuppression Immunotherapeutic agent Immunotherapy In Vitro Infiltration Inflammatory Interruption Lead Ligands MAP Kinase Gene MEK inhibition MEKs Malignant Neoplasms Malignant neoplasm of pancreas Mediating Methods Michigan Modality Myelogenous Myeloid Cells Myeloid-derived suppressor cells Neoplasm Metastasis Neoplasm Transplantation Organoids PD-1/PD-L1 Pancreas Pancreatic Ductal Adenocarcinoma Patients Phenotype Pre-Clinical Model Process Research Research Personnel Research Proposals Role STAT3 gene Schools Scientist Series Signal Transduction System T-Lymphocyte Testing Therapeutic Transplantation Tumor-associated macrophages Universities Work Xenograft procedure anti-tumor immune response arginase base cancer cell cancer immunotherapeutics cancer therapy checkpoint therapy combat cytokine experience fighting immune checkpoint in vivo inhibitor/antagonist innovation intercellular communication macrophage medical schools neoplastic cell novel pancreatic cancer cells pancreatic neoplasm polarized cell programmed cell death ligand 1 programmed cell death protein 1 recombinase response scaffold tumor tumor growth tumor microenvironment tumor-immune system interactions

项目摘要

Abstract Immune therapy has shown great promise in the treatment of a number of malignancies, but has not proven fruitful in fighting pancreatic ductal adenocarcinoma (PDA) using current modalities. One possible reason for this is the unique biology of the pancreatic cancer in establishing an immune suppressive microenvironment. We find that cross communication between cancer associated fibroblasts (CAFs), tumor associated macrophages (TAMs) and tumor cells is critical. Using animal models of PDA, we find that tumor cells polarize macrophages to TAMs both by activating CAFs to produce IL6 and by producing specific metabolites. TAMs then both suppress the immune response by arginine depletion by making Arginase 1 and by producing EGFR ligands, primarily HBEGF, to stimulate pancreatic cancer cells to express PDL1, an immune checkpoint ligand. We propose to use a combination of matched humanized patient derived xenografts (PDXs), organoid culture systems made up of cancer cells, immune cells and CAFs (ie “microtumors”) and a unique dual recombinase genetically engineered mouse model of PDA to test the hypothesis that treatment of tumors with inhibitors of STAT3, HBEGF, ARG1 or MEK will effectively synergize with PD1 inhibition, overcoming the powerful immune suppression created by the pancreatic cancer microenvironment.

摘要免疫疗法在许多恶性肿瘤的治疗中显示出巨大的前景，但目前在治疗胰腺导管腺癌(PDA)方面尚未被证明是有效的医疗模式。其中一个可能的原因是胰腺癌独特的生物学特性建立免疫抑制微环境。我们发现这种交叉交流肿瘤相关成纤维细胞(CAF)、肿瘤相关巨噬细胞(TAMs)和肿瘤细胞是至关重要的。使用PDA的动物模型，我们发现肿瘤细胞极化巨噬细胞通过激活CAF产生IL-6和通过产生特异性IL-6而产生TAM 代谢物。然后，TAMS和TAMs都通过产生精氨酸来抑制免疫反应精氨酸酶1和通过产生EGFR配体，主要是HBEGF来刺激胰腺癌细胞表达免疫检查点配体PDL1。我们建议结合使用匹配的人源化患者来源异种移植(PDX)，由以下组成的有机培养系统癌细胞、免疫细胞和CAF(即“微肿瘤”)和一种独特的双重重组酶用基因工程的小鼠PDA模型来验证这样一种假设，即用 STAT3、HBEGF、ARG1或MEK的抑制剂将与PD1抑制有效地协同作用，克服胰腺癌造成的强大免疫抑制微环境。