Pancreatic Stellate Cell (PSC) Engagement of Natural Killer (NK) cells in the Pancreatic Ductal Adenocarcinoma (PDAC) Tumor Microenvironment

胰腺星状细胞 (PSC) 与胰腺导管腺癌 (PDAC) 肿瘤微环境中自然杀伤 (NK) 细胞的参与

• 批准号: 10704009
• 负责人: Zoe Xenos Malchiodi
• 金额: $ 3.5万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10704009
• 关键词: Activated Natural Killer Cell; Biology; Blocking Antibodies; Cell Communication; Cell physiology; Cells; Cellular biology; Clinical; Combined Modality Therapy; Cytolysis; Cytometry; Data; Desmoplastic; Epithelial Cells; Exhibits; Fibroblasts; Fibrosis; Flow Cytometry; Future; Genetic Transcription; Growth; Human; Human Cell Line; Image; Immune; Immunologics; Immunosuppression; Immunotoxins; In Vitro; Inflammatory; Innate Immune System; Invaded; Knowledge; Laboratories; Ligands; Link; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mica; Molecular; Mus; Myofibroblast; Natural Killer Cells; Outcome; Pancreatic Ductal Adenocarcinoma; Patients; Phenotype; Population; Property; Receptor Cell; Rest; Role; Survival Rate; System; T-Lymphocyte; Therapeutic; Therapeutic Agents; Therapeutic Effect; Tissue Microarray; Tumor Burden; Tumor Promotion; Tumor Tissue; Tumor Volume; Work; anti-tumor immune response; antitumor effect; cancer cell; cell motility; cytotoxic; fibroblast-activating factor; immune resistance; immunogenic; in vivo; mouse model; neoplastic cell; novel; novel therapeutic intervention; pancreatic ductal adenocarcinoma cell; pancreatic ductal adenocarcinoma model; pancreatic stellate cell; prevent; resistance mechanism; single-cell RNA sequencing; spatial relationship; tissue repair; translational potential; tumor; tumor growth; tumor microenvironment; tumor progression; tumor-immune system interactions

PROJECT SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer, with a 5-year survival rate of less than 10%. One of the hallmarks of PDAC is immune suppression, which is mediated in part by a heterogenous cancer-associated fibroblast (CAF) population, also termed pancreatic stellate cells (PSCs). PSCs can exist as both tumor-promoting and tumor-restrictive subpopulations. Our laboratory recently showed that human natural killer (NK) cells interact with and lyse activated PSCs via a NKG2D-MICA/B NK cell receptor- ligand interaction. NK cells are cytotoxic components of the innate immune system; their functions are highly understudied in PDAC. Our laboratory also had made the novel and potentially important observations that activated, cytotoxic, NK cells are relatively abundant in the PDAC tumor microenvironment (TME), and that high expression of NK cell markers correlates with better PDAC patient survival. Based on these observations, I hypothesize that one important role of PSCs is to divert NK cells from malignant epithelial PDAC cells in the tumor microenvironment (TME), protecting tumors from immune attack. Therefore, this project’s first aim is to explore the interactions between fibroblast activation protein (FAP)+ PSCs with NK cells in PDAC. NK cell receptor-ligand interactions that regulate NK cell-mediated lysis of FAP+ PSCs will be further studied in vitro. The spatial relationships between NK cells and FAP+ PSCs will also be defined using a human PDAC tumor microarray by Imaging Mass Cytometry. The second aim is to examine the impact of NK cells and FAP+ PSCs on tumor growth. In a murine PDAC model, FAP+ PSCs will be depleted using a FAP-specific catalytic immunotoxin to assess the impact of FAP+ PSC depletion on PDAC and NK cell invasion, phenotype, and function. NK cells will also be selectively depleted in a murine PDAC model in order to determine their impact on tumor growth, FAP+ PSC phenotype and function in the PDAC TME. This work will employ single-cell RNA sequencing analysis to assess transcriptional changes in the PDAC TME as a function of these depletion studies. Combinations of NK cell enhancement/activation with FAP+ PSC depletion will define the potential translational relevance for future therapy strategies. Successful completion of these aims will elucidate the relevance of NK cell-PSC interactions in PDAC and will lay the groundwork for exploiting the innate immune system to increase the efficacy of the anti-tumor immune response.

项目摘要/摘要 摘要胰腺导管腺癌是胰腺癌中最常见的一种，其生存期为5年。 利率低于10%。PDAC的特征之一是免疫抑制，这在一定程度上是由一种 异源肿瘤相关成纤维细胞(CAF)群体，也称为胰腺星状细胞(PSCs)。PSCS 可以作为促进肿瘤的亚群和限制肿瘤的亚群存在。我们的实验室最近显示 人类自然杀伤(NK)细胞通过NKG2D-MICA/B NK细胞受体与激活的PSCs相互作用并溶解。 配基相互作用。NK细胞是先天免疫系统的细胞毒性成分；它们的功能很强 在PDAC留学。我们的实验室也进行了新的和潜在的重要观察 在PDAC肿瘤微环境(TME)中，活化的、细胞毒的、NK细胞相对丰富， NK细胞标志物的高表达与PDAC患者较好的生存相关。基于这些 据观察，我推测PSCs的一个重要作用是将NK细胞从恶性上皮细胞中分流出来 肿瘤微环境(TME)中的PDAC细胞，保护肿瘤免受免疫攻击。因此，这 该项目的第一个目标是探索成纤维细胞激活蛋白(FAP)+PSCs与NK细胞之间的相互作用 在PDAC中。调节NK细胞介导的FAP+PSCs裂解的NK细胞受体-配体相互作用将进一步 在体外研究。NK细胞和FAP+PSCs之间的空间关系也将使用人类 PDAC肿瘤基因芯片的成像质量分析。第二个目标是检查NK细胞和 FAP+PSCs对肿瘤生长的影响。在小鼠PDAC模型中，FAP+PSCs将被FAP特异性耗尽 催化免疫毒素评估FAP+PSC耗竭对PDAC和NK细胞侵袭、表型、 和功能。在小鼠PDAC模型中，NK细胞也将被选择性地耗尽，以确定它们的影响 肿瘤生长、FAP+PSC在PDAC-TME中的表型和功能。这项工作将使用单细胞RNA 测序分析以评估作为这些耗竭研究的功能的PDAC TME的转录变化。 NK细胞增强/激活和FAP+PSC耗竭的组合将定义潜在的翻译 对未来治疗策略的相关性。这些目标的成功实现将阐明NK的相关性 细胞-PSC在PDAC中的相互作用，并将为利用天然免疫系统增加 抗肿瘤免疫反应的疗效。