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.

项目总结/摘要 胰腺导管腺癌（PDAC）是最常见的胰腺癌，生存期为5年 率低于10%。PDAC的标志之一是免疫抑制，其部分由免疫抑制因子介导。 异种癌症相关成纤维细胞（CAF）群，也称为胰腺星状细胞（PSC）。PSCs 可以作为肿瘤促进亚群和肿瘤限制亚群存在。我们的实验室最近表明， 人自然杀伤（NK）细胞通过NKG 2D-MICA/B NK细胞受体与活化PSC相互作用并裂解活化PSC， 配体相互作用NK细胞是先天性免疫系统的细胞毒性组分;它们的功能是高度依赖于免疫系统。 是PDAC的替补我们的实验室还进行了新的和潜在的重要观察 活化的细胞毒性NK细胞在PDAC肿瘤微环境（TME）中相对丰富， NK细胞标志物的高表达与PDAC患者更好的存活率相关。基于这些 根据观察，我假设PSC的一个重要作用是将NK细胞从恶性上皮细胞转移到恶性上皮细胞， PDAC细胞在肿瘤微环境（TME）中，保护肿瘤免受免疫攻击。因此本 该项目的第一个目标是探索成纤维细胞活化蛋白（FAP）+PSC与NK细胞之间的相互作用 在PDAC。将进一步研究调节NK细胞介导的FAP+ PSC裂解的NK细胞受体-配体相互作用。 在体外研究。NK细胞和FAP+ PSC之间的空间关系也将使用人免疫组织化学方法来定义。 PDAC肿瘤微阵列成像质谱细胞术。第二个目的是检查NK细胞的影响， FAP+ PSC对肿瘤生长的影响。在鼠PDAC模型中，FAP+ PSC将使用FAP特异性免疫抑制剂耗尽。 催化免疫毒素，以评估FAP+ PSC耗竭对PDAC和NK细胞侵袭，表型， 和功能NK细胞也将在鼠PDAC模型中被选择性耗尽，以确定它们的影响 PDAC TME中的肿瘤生长、FAP+ PSC表型和功能。这项工作将使用单细胞RNA 测序分析以评估PDAC TME中的转录变化作为这些消耗研究的函数。 NK细胞增强/活化与FAP+ PSC耗竭的组合将定义潜在的翻译表达。 与未来治疗策略的相关性。成功地完成这些目标将阐明纳戈尔诺-卡拉巴赫的相关性， PDAC中的细胞-PSC相互作用，并将为利用先天免疫系统增加 抗肿瘤免疫应答的功效。