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.

项目概要/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 异质癌症相关成纤维细胞 (CAF) 群体，也称为胰腺星状细胞 (PSC)。 PSC 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 人类自然杀伤 (NK) 细胞通过 NKG2D-MICA/B NK 细胞受体与激活的 PSC 相互作用并裂解激活的 PSC 配体相互作用。 NK 细胞是先天免疫系统的细胞毒性成分；他们的功能非常 就读于PDAC。我们的实验室还进行了新颖且可能重要的观察 PDAC 肿瘤微环境 (TME) 中激活的细胞毒性 NK 细胞相对丰富， NK 细胞标志物的高表达与 PDAC 患者更好的生存率相关。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中转移出来。 肿瘤微环境 (TME) 中的 PDAC 细胞，保护肿瘤免受免疫攻击。因此，这 该项目的首要目标是探索成纤维细胞激活蛋白 (FAP)+ PSC 与 NK 细胞之间的相互作用 在 PDAC 中。调节 NK 细胞介导的 FAP+ PSC 裂解的 NK 细胞受体-配体相互作用将进一步 体外研究。 NK 细胞和 FAP+ PSC 之间的空间关系也将使用人类定义 通过成像质谱细胞术检测 PDAC 肿瘤微阵列。第二个目的是检查 NK 细胞和 FAP+ PSC 对肿瘤生长的影响。在小鼠 PDAC 模型中，FAP+ PSC 将使用 FAP 特异性物质耗尽 催化免疫毒素来评估 FAP+ PSC 耗竭对 PDAC 和 NK 细胞侵袭、表型、 和功能。还将在小鼠 PDAC 模型中选择性地消耗 NK 细胞，以确定其影响 PDAC TME 中肿瘤生长、FAP+ PSC 表型和功能的影响。这项工作将使用单细胞 RNA 测序分析来评估 PDAC TME 中转录变化作为这些耗尽研究的函数。 NK 细胞增强/激活与 FAP+ PSC 消耗的组合将定义潜在的转化 与未来治疗策略的相关性。成功完成这些目标将阐明 NK 的相关性 PDAC 中的细胞-PSC 相互作用，将为利用先天免疫系统提高 抗肿瘤免疫反应的功效。