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: 10609813
• 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/10609813
• 关键词: Address; Aftercare; Aggressive behavior; Bioinformatics; Biological Models; Biometry; Biopsy; Blood; Cancer Etiology; Cell Separation; 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 Promotion; 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）现在是癌症相关死亡的第三主要原因 美国，仍然是美国退伍军人的致命疾病。尽管胰腺癌细胞显示出对 标准的化学治疗剂，大多数患者有时会产生抗性，导致生存率差。 据报道，髓样细胞可以介导化学疗法的抗性，但是这种机制 专门发生在人类中尚未阐明。此类研究由于新鲜而具有挑战性 生物环体获取，患者异质性和潜水肿瘤微环境。我建议解决 这些障碍是通过利用机会在内窥镜诊断活检期间获得标本的机会 （治疗）和手术切除（治疗后）。 在此提案中，我将开发一条新颖的管道来生成单细胞的全面数据集 在治疗前后，使用胰腺癌患者在治疗前后对人PDAC肿瘤进行了测序 Ann Arbor VA医疗系统。我还将在体外使用患者衍生的共文化系统来解析 PDAC中化学抗性的髓样介导的机制。总体假设是 化学疗法通过重新编程来改变胰腺癌的肿瘤微环境 可以探索本地和系统的免疫系统，如果更好地理解，可以探索 治疗抗性的机制。总体目标是发现髓样细胞在肿瘤中的作用 侵略性并识别推定的治疗靶标，以克服化学难治性疾病。 在AIM 1中，我将定义PDAC对患者肿瘤化疗的反应的免疫特征， 外周血的目的是将特征与疾病结局相关联。 AIM 1将使用单细胞RNA 纵向匹配的PDAC患者的测序，多重免疫染色和质量细胞仪 生物测量，允许对治疗和治疗后进行个性化的患者特定比较 国家。在AIM 2中，我将使用专利衍生的PDAC肿瘤器官和周围的共培养系统 髓样细胞剖析负责髓样介导的治疗耐药性的串扰。在这里我将测试 骨髓细胞和肿瘤上皮细胞之间候选配体受体对肿瘤侵袭性的作用 和阻力。 该建议支持匹配的无价的单细胞测序数据集的开发 PDAC患者的纵向前和治疗后肿瘤组织，以及用于体外平台 机械研究，完全允许对肿瘤微环境和 在这种致命疾病中提供新的免疫治疗靶标。此外，该提议将允许 使用来自Ann Arbor VA的强大的胰腺癌生物循环计划的开发 以前尚未开发用于翻译研究目的的退伍军人，目的是最终 为胰腺癌退伍军人建立精确的医学平台。最后，该建议将支持 我继续培训和发展，以确立自己是VA独立调查员 胰腺癌，一种致命疾病，用于退伍军人人口。