Systematic interrogation of the pancreatic cancer microenvironment in patient-derived specimens

系统研究患者来源标本中的胰腺癌微环境

• 批准号: 10242454
• 负责人: William C. Hahn
• 金额: $ 61.16万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 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/10242454
• 关键词: Aftercare; Atlases; Biology; Biopsy; Biopsy Specimen; CC chemokine receptor 2; CD8-Positive T-Lymphocytes; Cells; Chemotherapy and/or radiation; Clinical; Clinical Trials; Coculture Techniques; Combination immunotherapy; Combined Modality Therapy; Complex; Cytotoxic Chemotherapy; Cytotoxic agent; Dana-Farber Cancer Institute; Desmoplastic; Devices; Disease; Elements; Evaluation; Evolution; Excision; FLT3 ligand; Fibroblasts; Future; Genetic; Genetically Engineered Mouse; Genomics; Heterogeneity; Human; Immune; Immune response; Immunocompetent; Immunofluorescence Immunologic; Immunologist; Immunosuppression; Immunotherapy; Interferon Type II; Interleukin-15; Lung Adenocarcinoma; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Methods; Microfluidic Microchips; Microfluidics; Modeling; Mus; Myelogenous; Myeloid Cells; Myeloid-derived suppressor cells; Nature; Neoadjuvant Therapy; Non-Malignant; Oncologist; Paclitaxel; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patient-Focused Outcomes; Patients; Periodicity; Phase Ib/II Clinical Trial; Phenotype; Play; Pre-Clinical Model; Proteomics; Radiation; Radiation therapy; Randomized; Regimen; Renal Cell Carcinoma; Research; Resectable; Resolution; Role; Sampling; Specimen; Survival Rate; T cell response; T-Lymphocyte; Technology; Testing; Therapeutic; Therapeutic Agents; Tumor-infiltrating immune cells; cancer type; cell type; checkpoint inhibition; chemotherapy; cytokine; early phase clinical trial; effective therapy; gemcitabine; immune checkpoint blockade; immunomodulatory strategy; immunomodulatory therapies; immunoregulation; improved; inhibitor/antagonist; macrophage; melanoma; mouse model; multidisciplinary; neoplastic cell; novel; novel strategies; outcome forecast; pancreatic cancer patients; pre-clinical; prevent; programs; recruit; response; single-cell RNA sequencing; spatial relationship; success; targeted delivery; targeted treatment; therapeutic evaluation; transcriptome; transcriptome sequencing; transcriptomics; treatment research; tumor; tumor heterogeneity; tumor microenvironment; tumor-immune system interactions

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with a 5-year survival rate of only 8%. Despite success in other cancer types, immunotherapy approaches in PDAC have not shown efficacy. PDAC demonstrates a heterogeneous and immunosuppressive tumor microenvironment (TME) that is poorly understood and serves as a barrier to effective immunotherapy strategies in this disease. We propose that an improved understanding of the TME and novel approaches that target key tumor-stroma interactions will enable remodeling of the immunosuppressive TME to enhance the efficacy of current and future immunotherapy strategies. In particular, we believe that successful combination immunotherapy approaches in PDAC will include strategies that alter myeloid cells to relieve immunosuppression, cytotoxic therapies that target tumor cells to improve immune response, and agents that augment anti-tumor T cell activity. In this project, we will perform a comprehensive characterization of the PDAC TME in both primary and metastatic PDAC in the baseline untreated context as well as across multiple different clinical therapies. In Aim 1, we will utilize single-cell transcriptomic and proteomic technologies to provide a cellular atlas of the PDAC TME at unprecedented resolution. In Aim 2, we will examine how the PDAC TME changes with chemotherapy, radiation therapy and a novel CCR2 inhibitor that modulates macrophage recruitment in the TME. For these studies, we will utilize human samples derived from both resectable and metastatic patients on clinical trials at Dana-Farber Cancer Institute. We will employ a novel ex vivo co-culture approach to enable rapid functional evaluation of tumor-stroma interactions and how they may impact immunotherapy responses. Lastly, in Aim 3 we will employ faithful immune competent PDAC mouse models and a novel cytokine delivery platform to investigate how targeted cytokine delivery to the TME may alter myeloid cell recruitment and function and improve immune responses. We have assembled a multi-disciplinary collaborative team including experts in PDAC biology and genetics, immunologists and translational oncologists to comprehensively study PDAC TME and identify novel opportunities to develop combination immunotherapy approaches in this devastating disease.

摘要 胰腺导管腺癌（PDAC）是一种致命的疾病，5年生存率仅为8%。尽管 尽管免疫疗法在其他癌症类型中取得了成功，但PDAC中的免疫疗法方法尚未显示出功效。PDAC 显示了异质性和免疫抑制性肿瘤微环境（TME）， 理解并作为有效的免疫治疗策略在这种疾病的障碍。我们建议， 提高对TME的理解和针对关键肿瘤-间质相互作用的新方法将 能够重塑免疫抑制性TME，以增强当前和未来的疗效， 免疫治疗策略。特别是，我们认为，成功的联合免疫治疗方法， PDAC将包括改变骨髓细胞以缓解免疫抑制的策略， 靶向肿瘤细胞以改善免疫应答，以及增强抗肿瘤T细胞活性的药剂。在这 项目，我们将在原发性和转移性PDAC TME中进行全面表征。 基线未治疗背景下以及多种不同临床治疗中的PDAC。在目标1中，我们 利用单细胞转录组学和蛋白质组学技术提供PDAC TME的细胞图谱， 前所未有的决心。在目标2中，我们将研究PDAC TME如何随着化疗而变化， 放射治疗和一种新的CCR 2抑制剂，调节TME中的巨噬细胞募集。为这些 研究中，我们将利用来自可切除和转移患者的人体样本进行临床试验， 丹娜-法伯癌症研究所。我们将采用一种新的离体共培养方法，使快速功能性 评估肿瘤-间质相互作用以及它们如何影响免疫治疗反应。在Aim 3中 我们将采用可靠的免疫活性PDAC小鼠模型和一种新的细胞因子递送平台， 研究靶向细胞因子递送至TME如何改变骨髓细胞募集和功能， 提高免疫反应。我们已经组建了一个多学科的合作团队，包括专家， PDAC生物学和遗传学，免疫学家和转化肿瘤学家全面研究PDAC TME 并确定新的机会，开发联合免疫治疗方法，在这一破坏性的 疾病