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