The Tumor Immune Microenvironment in Pancreatic Cancer Chemoresistance

胰腺癌化疗耐药中的肿瘤免疫微环境

• 批准号: 10363075
• 负责人: Eileen S Carpenter
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10363075
• 关键词: Address; Aftercare; Aggressive behavior; Bioinformatics; Biological Models; Biometry; Biopsy; Blood; Cancer Etiology; Cells; Cessation of life; Chemoresistance; Clinic; Clinical Data; Coculture Techniques; Consent; Cytometry; Data; Data Set; Development; Diagnosis; Diagnostic; Disease; Disease Outcome; Epithelial Cells; Excision; Fine-needle biopsy; Goals; Healthcare Systems; Heterogeneity; Human; IL8 gene; Immune; Immune response; Immune system; Immunofluorescence Immunologic; Immunotherapeutic agent; Impairment; In Vitro; Incidence; Legal patent; Ligands; Malignant neoplasm of pancreas; Mediating; Mus; Myelogenous; Myeloid Cells; Myeloproliferative disease; Operative Surgical Procedures; Organoids; Pancreatic Ductal Adenocarcinoma; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Play; Predisposition; Refractory; Refractory Disease; Reporting; Research Personnel; Resistance; Resistance development; Resources; Role; Sampling; Site; Specimen; Survival Rate; System; Techniques; Testing; Time; Tissues; Training; Translational Research; Translations; Tumor Tissue; Veterans; career; chemotherapeutic agent; chemotherapy; genetic signature; immune resistance; inhibitor; military veteran; neoplastic cell; novel; outcome prediction; pancreatic cancer cells; pancreatic cancer patients; peripheral blood; precision medicine; programs; receptor; response; single cell sequencing; single-cell RNA sequencing; therapeutic target; translational cancer research; treatment comparison; treatment response; tumor; tumor immunology; tumor microenvironment; tumor-immune system interactions

Pancreatic ductal adenocarcinoma (PDAC) is now the 3rd leading cause of cancer-related death in the US and remains a deadly disease for US veterans. Although pancreatic cancer cells show susceptibility to standard chemotherapeutic agents, most patients eventually develop resistance, leading to poor survival. Myeloid cells have been reported to mediate chemotherapy resistance, however the mechanisms by which this occurs specifically in humans have yet to be elucidated. Such studies are challenging due to fresh biospecimen acquisition, patient heterogeneity, and a diverse tumor microenvironment. I propose to address these obstacles by exploiting opportunities to obtain specimens during endoscopic diagnostic biopsy (treatment-naïve) and surgical resection (post-treatment). In this proposal, I will develop a novel pipeline to generate a comprehensive dataset of single-cell sequenced human PDAC tumors longitudinally, before and after treatment, using pancreatic cancer patients at the Ann Arbor VA Healthcare System. I will also use a patient-derived co-culture system in vitro to parse out the myeloid-mediated mechanisms of chemoresistance in PDAC. The overarching hypothesis is that chemotherapy alters the tumor microenvironment in pancreatic cancer through reprogramming of the local and systemic immune system, and if better understood, can be exploited to uncover mechanisms of therapy resistance. The overall goal will be to uncover the role of myeloid cells in tumor aggressiveness and identify putative therapeutic targets to overcome chemo-refractory disease. In Aim 1, I will define immune signatures of PDAC response to chemotherapy in patient tumors and peripheral blood with the goal of correlating signatures to disease outcomes. Aim 1 will utilize single-cell RNA sequencing, multiplex immunostaining, and mass cytometry on longitudinal matched PDAC patient biospecimens, allowing for an individualized patient-specific comparison of treatment-naïve and post-treatment states. In Aim 2, I will use a patent-derived co-culture system of PDAC tumor organoids and peripheral myeloid cells to dissect the crosstalk responsible for myeloid-mediated therapy resistance. Here I will test the role of candidate ligand-receptors pairs between myeloid cells and tumor epithelial cells in tumor aggression and resistance. This proposal supports the development of an invaluable single-cell sequencing dataset of matched longitudinal pre- and post-treatment tumor tissue in PDAC patients, as well as an in vitro platform for mechanistic studies, altogether allowing for a comprehensive study of the tumor microenvironment and providing new immunotherapeutic targets in this deadly disease. Furthermore, this proposal will allow for the development of a robust pancreatic cancer biospecimen program at the Ann Arbor VA using samples from veterans that have previously been untapped for translational research purposes, with the goal of eventually building a precision medicine platform for veterans with pancreatic cancer. Finally, this proposal will support my continued training and development to establish myself as a VA independent investigator in the field of pancreatic cancer, a deadly disease for the veteran population.

胰腺导管腺癌 (PDAC) 目前是癌症相关死亡的第三大原因 尽管胰腺癌细胞表现出易感性，但对美国退伍军人来说仍然是一种致命的疾病。 标准化疗药物，大多数患者最终会产生耐药性，导致生存率低。 据报道，骨髓细胞可以介导化疗耐药性，但是这种机制的机制 由于新鲜，此类研究具有挑战性。 我建议解决生物样本采集、患者异质性和多样化的肿瘤微环境。 通过在内窥镜诊断活检期间利用获取标本的机会来克服这些障碍 （未经治疗）和手术切除（治疗后）。 在这个提案中，我将开发一种新颖的管道来生成单细胞的综合数据集 使用胰腺癌患者在治疗前和治疗后对人类 PDAC 肿瘤进行纵向测序 我还将使用患者来源的体外共培养系统来解析。 PDAC 中骨髓介导的化疗耐药机制的总体假设是： 化疗通过重新编程改变胰腺癌的肿瘤微环境 局部和全身免疫系统，如果更好地理解，可以用来发现 治疗耐药机制的总体目标是揭示骨髓细胞在肿瘤中的作用。 攻击性并确定克服化疗难治性疾病的假定治疗靶点。 在目标 1 中，我将定义 PDAC 对患者肿瘤化疗反应的免疫特征，以及 目标 1 将利用单细胞 RNA 来检测外周血，以将特征与疾病结果相关联。 对纵向匹配的 PDAC 患者进行测序、多重免疫染色和质谱流式分析 生物样本，允许对未接受治疗和治疗后的个体化患者进行比较 在目标 2 中，我将使用 PDAC 肿瘤类器官和外周血的专利共培养系统。 骨髓细胞来剖析导致骨髓介导的治疗耐药性的串扰。 骨髓细胞和肿瘤上皮细胞之间候选配体-受体对在肿瘤侵袭中的作用 和阻力。 该提案支持开发一个宝贵的匹配单细胞测序数据集 PDAC 患者治疗前和治疗后的纵向肿瘤组织，以及体外平台 机制研究，总共可以对肿瘤微环境进行全面研究 此外，该提案还将为这种致命疾病提供新的免疫治疗靶点。 使用来自弗吉尼亚州安娜堡的样本开发强大的胰腺癌生物样本计划 以前未被用于转化研究目的的退伍军人，目标是最终 最后，该提案将支持为患有胰腺癌的退伍军人建立精准医疗平台。 我继续接受培训和发展，使自己成为 VA 领域的独立调查员 胰腺癌，对于退伍军人来说是一种致命的疾病。