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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：
9449550
负责人：
Howard C Crawford
金额：
$ 149.76万
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 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9449550
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 Feedback Fibroblasts Genetically Engineered Mouse Goals Growth Factor Human IL6 gene Immune Immune checkpoint inhibitor Immune response Immune system Immunosuppression Immunosuppressive Agents Immunotherapeutic agent Immunotherapy In Vitro Infiltration Inflammatory Interruption Lead Ligands MAP Kinase Gene MEK inhibition Malignant Neoplasms Malignant neoplasm of pancreas Mediating Methods Michigan Modality Myelogenous Myeloid Cells Neoplasm Metastasis Neoplasm Transplantation Organoids PDCD1LG1 gene Pancreas Pancreatic Ductal Adenocarcinoma Patients Phenotype Pre-Clinical Model Process Research Research Personnel Research Proposals Role STAT3 gene Schools Scientist Series Signal Transduction Suppressor-Effector T-Lymphocytes System T-Lymphocyte Testing Therapeutic Transplantation Universities Work Xenograft procedure arginase base cancer cell cancer therapy cell growth checkpoint therapy combat cytokine experience fighting immune checkpoint in vivo inhibitor/antagonist innovation intercellular communication macrophage medical schools mouse model neoplastic cell novel pancreatic cancer cells pancreatic neoplasm polarized cell recombinase response scaffold tumor tumor growth tumor microenvironment

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.

抽象的免疫疗法在治疗多种恶性肿瘤方面显示出巨大的前景，但尚未证明使用目前的方法在对抗胰腺导管腺癌（PDA）方面取得成果方式。造成这种情况的一个可能原因是胰腺癌的独特生物学特性建立免疫抑制微环境。我们发现交叉沟通癌症相关成纤维细胞（CAF）、肿瘤相关巨噬细胞（TAM）和肿瘤细胞至关重要。使用PDA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 IL6 和产生特定的 TAM 来激活 TAM 代谢物。然后 TAM 都会通过精氨酸消耗来抑制免疫反应精氨酸酶 1 并通过产生 EGFR 配体（主要是 HBEGF）来刺激胰腺癌细胞表达 PDL1（一种免疫检查点配体）。我们建议结合使用匹配的人源化异种移植物（PDX），类器官培养系统由癌细胞、免疫细胞和 CAF（即“微肿瘤”）和独特的双重组酶基因工程小鼠 PDA 模型来检验用 PDA 治疗肿瘤的假设 STAT3、HBEGF、ARG1 或 MEK 抑制剂将有效地协同 PD1 抑制，克服胰腺癌造成的强大免疫抑制微环境。