PT - JOURNAL ARTICLE AU - López-Gil, Juan Carlos AU - García-Silva, Susana AU - Ruiz-Cañas, Laura AU - Navarro, Diego AU - Palencia-Campos, Adrián AU - Giráldez-Trujillo, Antonio AU - Earl, Julie AU - Dorado, Jorge AU - Gómez-López, Gonzalo AU - Monfort-Vengut, Ana AU - Alcalá, Sonia AU - Gaida, Matthias M AU - García-Mulero, Sandra AU - Cabezas-Sáinz, Pablo AU - Batres-Ramos, Sandra AU - Barreto, Emma AU - Sánchez-Tomero, Patricia AU - Vallespinós, Mireia AU - Ambler, Leah AU - Lin, Meng-Lay AU - Aicher, Alexandra AU - García García de Paredes, Ana AU - de la Pinta, Carolina AU - Sanjuanbenito, Alfonso AU - Ruz-Caracuel, Ignacio AU - Rodríguez-Garrote, Mercedes AU - Guerra, Carmen AU - Carrato, Alfredo AU - de Cárcer, Guillermo AU - Sánchez, Laura AU - Nombela-Arrieta, César AU - Espinet, Elisa AU - Sanchez-Arevalo Lobo, Víctor Javier AU - Heeschen, Christopher AU - Sainz, Bruno TI - The Peptidoglycan Recognition Protein 1 confers immune evasive properties on pancreatic cancer stem cells AID - 10.1136/gutjnl-2023-330995 DP - 2024 May 14 TA - Gut PG - gutjnl-2023-330995 4099 - http://gut.bmj.com/content/early/2024/05/14/gutjnl-2023-330995.short 4100 - http://gut.bmj.com/content/early/2024/05/14/gutjnl-2023-330995.full AB - 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 (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.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.Data are available in a public, open access repository. Transcriptional data generated in this study from expression microarrays have been deposited in GEO database with accession number ID: GSE222986. Additional publicly available dataset references: Schlesinger Y, Yosefov-Levi O, Kolodkin-Gal D, Granit RZ, Peters L, Kalifa R, et al. Single-cell transcriptomes of pancreatic preinvasive lesions and cancer reveal acinar metaplastic cells’ heterogeneity. Nat Commun. 2020;11(1):4516.38. Nicolle R, Raffenne J, Paradis V, Couvelard A, de Reynies A, Blum Y, et al. Prognostic Biomarkers in Pancreatic Cancer: Avoiding Errata When Using the TCGA Dataset. Cancers. 2019;11(1).40. Espinet E, Gu Z, Imbusch CD, Giese NA, Büscher M, Safavi M, et al. Aggressive PDACs Show Hypomethylation of Repetitive Elements and the Execution of an Intrinsic IFN Program Linked to a Ductal Cell of Origin. Cancer discovery. 2021;11(3):638-59.41. Hwang WL, Jagadeesh KA, Guo JA, Hoffman HI, Yadollahpour P, Reeves JW, et al. Single-nucleus and spatial transcriptome profiling of pancreatic cancer identifies multicellular dynamics associated with neoadjuvant treatment. Nature genetics. 2022;54(8):1178-91.43. Martinelli P, Carrillo-de Santa Pau E, Cox T, Sainz B, Jr., Dusetti N, Greenhalf W, et al. GATA6 regulates EMT and tumour dissemination, and is a marker of response to adjuvant chemotherapy in pancreatic cancer. Gut. 2017;66(9):1665-76.44. Moffitt RA, Marayati R, Flate EL, Volmar KE, Loeza SG, Hoadley KA, et al. Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of PDAC. Nature genetics. 2015;47(10):1168-78.45. Janky R, Binda MM, Allemeersch J, Van den Broeck A, Govaere O, Swinnen JV, et al. Prognostic relevance of molecular subtypes and master regulators in PDAC. BMC Cancer. 2016;16:632.