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Fatty acid signaling in the pancreatic tumor microenvironment

胰腺肿瘤微环境中的脂肪酸信号传导

基本信息

批准号：
10728646
负责人：
Mara H. Sherman
金额：
$ 48.68万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-12 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10728646
关键词：
Antineoplastic Agents Arachidonic Acids Aspartate Transaminase Binding Biological Assay Biology CD8-Positive T-Lymphocytes Cell Proliferation Chromatin Clinical Coculture Techniques Combined Modality Therapy Complex DNA Sequence Alteration Data Development Disease Enhancers Enzymes Exclusion Fatty Acids Fostering Gene Expression Gene Expression Regulation Genes Genetic Genetic Transcription Goals Growth Heterogeneity Immune Immune Evasion Immune system Immunosuppression Immunotherapy In Vitro Infiltration Inflammatory Ligands Link Lymphoid Malate-Aspartate Shuttle Pathway Malignant neoplasm of pancreas Mediating Mitochondria Molecular Myelogenous Myeloid Cells Myeloid-derived suppressor cells Nuclear Receptors Outcome Pancreatic Ductal Adenocarcinoma Pathway interactions Patient-Focused Outcomes Patients Pattern Phenotype Process Productivity Proteins Regulation Role Shapes Signal Transduction Solid Neoplasm Specimen Stromal Neoplasm System T-Lymphocyte Testing Therapeutic Therapeutic Intervention Transcriptional Regulation Tumor Immunity Tumor Promotion Tumor Suppression Work anti-tumor immune response cancer cell clinical translation conventional therapy druggable target experimental study genome-wide immunomodulatory therapies immunoregulation improved improved outcome in vivo inhibitor mouse model mutant mutational status novel novel therapeutics pancreatic cancer cells pancreatic ductal adenocarcinoma cell pancreatic neoplasm paracrine patient population permissiveness pharmacologic precision medicine preclinical evaluation prevent programs rational design transcription factor tumor tumor growth tumor microenvironment tumor-immune system interactions

项目摘要

PROJECT SUMMARY/ABSTRACT Despite significant recent advances in precision medicine, pancreatic ductal adenocarcinoma (PDAC) remains near-uniformly lethal. While the most frequent genomic alterations in PDAC are not presently druggable and conventional therapies are often ineffective in this disease, immune-modulatory therapies hold promise to meaningfully improve outcomes for PDAC patients. Development of such therapies requires an improved understanding of the immune evasion mechanisms that characterize the PDAC microenvironment, including frequent exclusion of antineoplastic T cells and abundance of immune-suppressive myeloid cells. We recently found that cancer cell-intrinsic glutamic-oxaloacetic transaminase 2 (GOT2) shapes the immune microenvironment to suppress antitumor immunity. Mechanistically, we found that GOT2 functions beyond its established role in the malate-aspartate shuttle and promotes the transcriptional activity of nuclear receptor PPARd, facilitated by direct binding to PPARd ligand arachidonic acid. While GOT2 in PDAC cells is dispensable for cancer cell proliferation in vivo, GOT2 loss results in T cell-dependent suppression of tumor growth, and genetic or pharmacologic PPARd activation restores PDAC progression in the GOT2-null context. This cancer cell-intrinsic GOT2-PPARd axis promotes spatial restriction of both CD4 and CD8 T cells from the tumor microenvironment, and fosters the immune-suppressive phenotype of tumor-infiltrating myeloid cells. Our results to date demonstrate a non-canonical function for an established mitochondrial enzyme in transcriptional regulation of immune evasion, and here we propose to exploit this novel GOT2-PPARd axis to promote a productive antitumor immune response with the following specific aims. Aim 1: Assess the therapeutic potential of targeting the GOT2-PPARd axis in established PDAC. We will perform preclinical evaluation of GOT2/PPARd pathway inhibition together with therapeutic approaches aimed to increase antitumor T cell activity in diverse mouse models, validate our findings in patient specimens with known clinical outcomes and mutational status, and assess heterogeneity across the patient population with respect to the association between GOT2 signaling and T cell spatial regulation. Aim 2: Analyze the immune evasion mechanisms driven by cancer cell-intrinsic GOT2. We will apply in vitro co-culture systems, in vivo assays testing a suite of GOT2 mutants with varying fatty acid signaling capacity, and unbiased transcriptional analyses to understand the stepwise mechanisms mediating paracrine regulation of immune evasion. Aim 3: Interrogate fatty acid-mediated gene regulation by GOT2 and PPARd. We will analyze the genome-wide binding patterns of PPARd and additional immune-modulatory transcription factors putatively regulated by GOT2, and characterize chromatin states in the context of fatty acid signaling perturbations that prevent or permit antitumor immune responses. This work will leverage our recent identification of a novel immune suppression mechanism in PDAC, with the potential to inform on new therapeutic combinations poised for clinical translation.

项目概要/摘要尽管精准医学最近取得了重大进展，但胰腺导管腺癌（PDAC）仍然存在几乎一致致命。虽然 PDAC 中最常见的基因组改变目前无法通过药物治疗，传统疗法通常对这种疾病无效，免疫调节疗法有望治愈这种疾病有意义地改善 PDAC 患者的治疗结果。此类疗法的开发需要改进了解表征 PDAC 微环境的免疫逃避机制，包括经常排除抗肿瘤 T 细胞和大量免疫抑制性骨髓细胞。我们最近发现癌细胞固有的谷氨酸草酰乙酸转氨酶 2 (GOT2) 塑造免疫抑制抗肿瘤免疫的微环境。从机制上讲，我们发现 GOT2 的功能超出了它的功能在苹果酸-天冬氨酸穿梭中发挥作用并促进核受体的转录活性 PPARd，通过直接结合 PPARd 配体花生四烯酸而促进。而PDAC细胞中的GOT2是可有可无的对于体内癌细胞增殖，GOT2 缺失会导致 T 细胞依赖性肿瘤生长抑制，并且遗传或药理学 PPARd 激活可恢复 GOT2 缺失背景下的 PDAC 进展。这种癌症细胞固有的 GOT2-PPARd 轴促进肿瘤中 CD4 和 CD8 T 细胞的空间限制微环境，并促进肿瘤浸润骨髓细胞的免疫抑制表型。我们的成果迄今为止，证明了转录中已建立的线粒体酶的非规范功能免疫逃避的调节，在这里我们建议利用这种新型的 GOT2-PPARd 轴来促进具有以下特定目标的有效抗肿瘤免疫反应。目标 1：评估治疗效果在已建立的 PDAC 中靶向 GOT2-PPARd 轴的潜力。我们将进行临床前评估 GOT2/PPARd 通路抑制以及旨在增加抗肿瘤 T 细胞活性的治疗方法在不同的小鼠模型中，验证我们在具有已知临床结果和突变的患者标本中的发现状态，并评估患者群体中 GOT2 之间关联的异质性信号传导和 T 细胞空间调节。目标2：分析癌症驱动的免疫逃避机制细胞固有的 GOT2。我们将应用体外共培养系统、体内分析测试一套 GOT2 突变体具有不同的脂肪酸信号传导能力，以及无偏见的转录分析以了解逐步介导免疫逃避的旁分泌调节的机制。目标 3：探究脂肪酸介导的基因 GOT2 和 PPARd 的调节。我们将分析 PPARd 和其他基因组的结合模式免疫调节转录因子可能受 GOT2 调节，并表征染色质状态阻止或允许抗肿瘤免疫反应的脂肪酸信号传导扰动的背景。这项工作将利用我们最近在 PDAC 中发现的一种新型免疫抑制机制，有可能为临床转化做好准备的新治疗组合提供信息。