López-Gil Juan Carlos, García-Silva Susana, Ruiz-Cañas Laura, Navarro Diego, Palencia-Campos Adrián, Giráldez-Trujillo Antonio, Earl Julie, Dorado Jorge, Gómez-López Gonzalo, Monfort-Vengut Ana, Alcalá Sonia, Gaida Matthias M, García-Mulero Sandra, Cabezas-Sáinz Pablo, Batres-Ramos Sandra, Barreto Emma, Sánchez-Tomero Patricia, Vallespinós Mireia, Ambler Leah, Lin Meng-Lay, Aicher Alexandra, García García de Paredes Ana, de la Pinta Carolina, Sanjuanbenito Alfonso, Ruz-Caracuel Ignacio, Rodríguez-Garrote Mercedes, Guerra Carmen, Carrato Alfredo, de Cárcer Guillermo, Sánchez Laura, Nombela-Arrieta César, Espinet Elisa, Sanchez-Arevalo Lobo Víctor Javier, Heeschen Christopher, Sainz Bruno
Cancer Stem Cells and Fibroinflammatory Microenvironment Group, Cancer Department, Instituto de Investigaciones Biomédicas (IIBM) Sols-Morreale CSIC-UAM, Madrid, Spain.
Biomarkers and Personalized Approach to Cancer Group (BIOPAC), Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.
Gut. 2024 Aug 8;73(9):1489-1508. doi: 10.1136/gutjnl-2023-330995.
Pancreatic ductal adenocarcinoma (PDAC) has limited therapeutic options, particularly with immune checkpoint inhibitors. Highly chemoresistant 'stem-like' cells, known as cancer stem cells (CSCs), are implicated in PDAC aggressiveness. Thus, comprehending how this subset of cells evades the immune system is crucial for advancing novel therapies.
We used the KPC mouse model () and primary tumour cell lines to investigate putative CSC populations. Transcriptomic analyses were conducted to pinpoint new genes involved in immune evasion. Overexpressing and knockout cell lines were established with lentiviral vectors. Subsequent coculture assays, mouse and zebrafish tumorigenesis studies, and database approaches were performed.
Using the KPC mouse model, we functionally confirmed a population of cells marked by EpCAM, Sca-1 and CD133 as authentic CSCs and investigated their transcriptional profile. Immune evasion signatures/genes, notably the gene peptidoglycan recognition protein 1 (PGLYRP1), were significantly overexpressed in these CSCs. Modulating PGLYRP1 impacted CSC immune evasion, affecting their resistance to macrophage-mediated and T-cell-mediated killing and their tumourigenesis in immunocompetent mice. Mechanistically, tumour necrosis factor alpha (TNFα)-regulated PGLYRP1 expression interferes with the immune tumour microenvironment (TME) landscape, promoting myeloid cell-derived immunosuppression and activated T-cell death. Importantly, these findings were not only replicated in human models, but clinically, secreted PGLYRP1 levels were significantly elevated in patients with PDAC.
This study establishes PGLYRP1 as a novel CSC-associated marker crucial for immune evasion, particularly against macrophage phagocytosis and T-cell killing, presenting it as a promising target for PDAC immunotherapy.
胰腺导管腺癌（PDAC）的治疗选择有限，尤其是免疫检查点抑制剂。具有高度化学抗性的“干细胞样”细胞，即癌症干细胞（CSC），与PDAC的侵袭性有关。因此，了解这一细胞亚群如何逃避免疫系统对于推进新疗法至关重要。
我们使用KPC小鼠模型和原发性肿瘤细胞系来研究假定的CSC群体。进行转录组分析以确定参与免疫逃逸的新基因。用慢病毒载体建立过表达和基因敲除细胞系。随后进行共培养试验、小鼠和斑马鱼肿瘤发生研究以及数据库分析。
使用KPC小鼠模型，我们在功能上确认了以EpCAM、Sca-1和CD133标记的细胞群体为真正的CSC，并研究了它们的转录谱。免疫逃逸特征/基因，特别是肽聚糖识别蛋白1（PGLYRP1）基因，在这些CSC中显著过表达。调节PGLYRP1会影响CSC的免疫逃逸，影响它们对巨噬细胞介导和T细胞介导杀伤的抗性以及它们在免疫健全小鼠中的肿瘤发生。从机制上讲，肿瘤坏死因子α（TNFα）调节的PGLYRP1表达会干扰免疫肿瘤微环境（TME）格局，促进髓系细胞衍生的免疫抑制和活化T细胞死亡。重要的是，这些发现不仅在人类模型中得到了重复，而且在临床上，PDAC患者的分泌型PGLYRP1水平显著升高。
本研究确定PGLYRP1是一种与CSC相关的新型标志物，对免疫逃逸至关重要，尤其是对巨噬细胞吞噬和T细胞杀伤具有抗性，使其成为PDAC免疫治疗的一个有前景的靶点。
