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oai:repisalud.isciii.es:20.500.12105/230792024-11-28T16:11:31Zcom_20.500.12105_2173com_20.500.12105_2051com_20.500.12105_15322col_20.500.12105_19597col_20.500.12105_16938col_20.500.12105_16962col_20.500.12105_16988

00925njm 22002777a 4500 dc López-Gil, Juan Carlos author García-Silva, Susana author Ruiz-Cañas, Laura author Navarro, Diego author Palencia-Campos, Adrián author Giráldez-Trujillo, Antonio author Earl, Julie author Dorado, Jorge author Gómez-López, Gonzalo author Monfort-Vengut, Ana author Alcalá, Sonia author Gaida, Matthias M author García-Mulero, Sandra author Cabezas-Sáinz, Pablo author Batres-Ramos, Sandra author Barreto, Emma author Sánchez-Tomero, Patricia author Vallespinós, Mireia author Ambler, Leah author Lin, Meng-Lay author Aicher, Alexandra author García García de Paredes, Ana author de la Pinta, Carolina author Sanjuanbenito, Alfonso author Ruz-Caracuel, Ignacio author Rodríguez-Garrote, Mercedes author Guerra, Carmen author Carrato, Alfredo author de Cárcer, Guillermo author Sánchez, Laura author Nombela-Arrieta, César author Espinet, Elisa author Sanchez-Arevalo Lobo, Víctor Javier author Heeschen, Christopher author Sainz, Bruno author 2024-08-08 OBJECTIVE: 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. DESIGN: We used the KPC mouse model (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre) 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 in vitro coculture assays, in vivo mouse and zebrafish tumorigenesis studies, and in silico database approaches were performed. RESULTS: 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 (TNF?)-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. CONCLUSIONS: 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. Gut . 2024 ;73(9):1489-1508. 10.1136/gutjnl-2023-330995 1468-3288 Gut 38754953 https://hdl.handle.net/20.500.12105/23079 The Peptidoglycan Recognition Protein 1 confers immune evasive properties on pancreatic cancer stem cells.