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The Peptidoglycan Recognition Protein 1 confers immune evasive properties on pancreatic cancer stem cells.

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dc.contributor.authorLópez-Gil, Juan Carlos
dc.contributor.authorGarcía-Silva, Susana
dc.contributor.authorRuiz-Cañas, Laura
dc.contributor.authorNavarro, Diego
dc.contributor.authorPalencia-Campos, Adrián
dc.contributor.authorGiráldez-Trujillo, Antonio
dc.contributor.authorEarl, Julie
dc.contributor.authorDorado, Jorge
dc.contributor.authorGómez-López, Gonzalo
dc.contributor.authorMonfort-Vengut, Ana
dc.contributor.authorAlcalá, Sonia
dc.contributor.authorGaida, Matthias M
dc.contributor.authorGarcía-Mulero, Sandra
dc.contributor.authorCabezas-Sáinz, Pablo
dc.contributor.authorBatres-Ramos, Sandra
dc.contributor.authorBarreto, Emma
dc.contributor.authorSánchez-Tomero, Patricia
dc.contributor.authorVallespinós, Mireia
dc.contributor.authorAmbler, Leah
dc.contributor.authorLin, Meng-Lay
dc.contributor.authorAicher, Alexandra
dc.contributor.authorGarcía García de Paredes, Ana
dc.contributor.authorde la Pinta, Carolina
dc.contributor.authorSanjuanbenito, Alfonso
dc.contributor.authorRuz-Caracuel, Ignacio
dc.contributor.authorRodríguez-Garrote, Mercedes
dc.contributor.authorGuerra, Carmen
dc.contributor.authorCarrato, Alfredo
dc.contributor.authorde Cárcer, Guillermo
dc.contributor.authorSánchez, Laura
dc.contributor.authorNombela-Arrieta, César
dc.contributor.authorEspinet, Elisa
dc.contributor.authorSanchez-Arevalo Lobo, Víctor Javier
dc.contributor.authorHeeschen, Christopher
dc.contributor.authorSainz, Bruno
dc.contributor.funderFundación La Caixaes_ES
dc.contributor.funderEMBO Scientific Exchange Fellowshipes_ES
dc.contributor.funderJuan de la Cierva Formaciones_ES
dc.contributor.funderFero Foundation Grantes_ES
dc.contributor.funderMinisterio de Economía y Competitividad (España)es_ES
dc.contributor.funderAsociación Española Contra el Cánceres_ES
dc.contributor.funderInstituto de Salud Carlos IIIes_ES
dc.contributor.funderUnión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)es_ES
dc.contributor.funderCentro de Investigación Biomédica en Red - CIBERONC (Cáncer)es_ES
dc.contributor.funderXunta de Galicia (España)es_ES
dc.contributor.funderUniversity of Zuriches_ES
dc.contributor.funderGerman Research Foundation (DFG)es_ES
dc.contributor.funderUnión Europea. Comisión Europea. European Research Council (ERC)es_ES
dc.contributor.funderFondazione AIRC per la ricerca sul cancroes_ES
dc.contributor.funderShanghai Municipal Education Commission (SHMEC)es_ES
dc.contributor.funderNational Natural Science Foundation of China (NSFC)es_ES
dc.date.accessioned2024-09-16T08:16:56Z
dc.date.available2024-09-16T08:16:56Z
dc.date.issued2024-08-08
dc.description.abstractOBJECTIVE: 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.es_ES
dc.description.peerreviewedSíes_ES
dc.description.sponsorshipJCL-G received support from a 'La Caixa' Foundation (ID 100010434) fellowship (LCF/BQ/DR21/11880011) and an EMBO Scientific Exchange Fellowship (ID 10210). AP-C was a recipient of a Juan de la Cierva Formacion 2020 (FJC2020-044220-I) grant. This study was supported by a Fero Foundation Grant (BSJr.) and Ramon y Cajal Merit Award (RYC-2012-12104) from the Ministerio de Economia y Competitividad, Spain (BSJr.); received funding from the Beca Carmen Delgado/Miguel Perez-Mateo from AESPANC-ACANPAN Spain (BSJr), a Conquer Cancer Now Grant from the Concern Foundation (Los Angeles, CA, USA) (BSJr), a Coordinated grant (GC16173694BARB) from the Fundacion Asociacion Espanola Contra el Cancer (AECC) (BSJr; AC), and FIS grants PI18/00757 and PI21/01110 (BSJr), PI19/00514 (CG) and PI22/00492 (VJSAL); and cofinanced through Fondo Europeo de Desarrollo Regional 'Una manera de hacer Europa'). We also acknowledge the support from CIBERONC (CB16/12/00446) (AC) and Ayudas de Consolidacion y Estructuracion de grupos from Conselleria de Educacion, Universidade y Formacion profesional (ED431C-2028/28) and Programa de axudas a etapa posdotoral, both from Xunta de Galicia (LS, PCS). Projects were financed via MCIN/ AEI/FEDER (10.13039/501100011033) (REF-PID2021-125705OB-I00 (GdC) and REF-RTI2018-095496-B-100) (GdC), and PID2021-124520OA-I00 and RYC2020-029767 (EE),and others including AECC (LABAE16017DECA, GdC and TRNSC213893ESPI, SG-M);the Clinical Research Priority Program 'ImmunoCure' of the University of Zurich (CN-A), the German Research Foundation (SFB1292 Project Number 318346496, TPQ1 and TP22), GA1818/2-3 (MMG) as well as funding from an ERC Advanced Investigator Grant (Pa-CSC 233460, CH), the European Community's Seventh Framework Programme (FP7) under grant agreement n degrees 602783 (CAM-PaC, CH), the Fondazione del Piemonte per l'Oncologia - IRCCS (PTCRC-Intra-2021, CH), the Fondazione AIRC per la ricerca sul cancro (IG 2023 ID 28933, CH), the Shanghai Municipal Education Commission (2021-01-07-00-02-E00090, CH), and the National Science Foundation China (82130074, CH).es_ES
dc.format.number9es_ES
dc.format.page1489es_ES
dc.format.volume73es_ES
dc.identifier.citationGut . 2024 ;73(9):1489-1508.es_ES
dc.identifier.doi10.1136/gutjnl-2023-330995es_ES
dc.identifier.e-issn1468-3288es_ES
dc.identifier.journalGutes_ES
dc.identifier.pubmedID38754953es_ES
dc.identifier.urihttps://hdl.handle.net/20.500.12105/23079
dc.language.isoenges_ES
dc.publisherBMJ Publishing Groupes_ES
dc.relation.projectFECYTinfo:eu-repo/grantAgreement/EC/FP7/602783/EUes_ES
dc.relation.projectFECYTinfo:eu-repo/grantAgreement/EC/FP7/228933/EUes_ES
dc.relation.projectFECYTinfo:eu-repo/grantAgreement/ES/PI18/00757es_ES
dc.relation.projectFECYTinfo:eu-repo/grantAgreement/ES/PI21/01110es_ES
dc.relation.projectFECYTinfo:eu-repo/grantAgreement/ES/PI19/00514es_ES
dc.relation.projectFECYTinfo:eu-repo/grantAgreement/ES/PI22/00492es_ES
dc.relation.projectFECYTinfo:eu-repo/grantAgreement/ES/CB16/12/00446es_ES
dc.relation.publisherversionhttps://doi.org/10.1136/gutjnl-2023-330995es_ES
dc.repisalud.institucionCNIOes_ES
dc.repisalud.orgCNIOCNIO::Grupos de investigación::Grupo de Oncología Experimentales_ES
dc.rights.accessRightsopen accesses_ES
dc.rights.licenseAttribution-NonCommercial-NoDerivatives 4.0 Internacional*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subject.meshPancreatic Neoplasmses_ES
dc.subject.meshNeoplastic Stem Cellses_ES
dc.subject.meshCarcinoma, Pancreatic Ductales_ES
dc.subject.meshAnimalses_ES
dc.subject.meshMicees_ES
dc.subject.meshHumanses_ES
dc.subject.meshCell Line, Tumores_ES
dc.subject.meshTumor Escapees_ES
dc.subject.meshDisease Models, Animales_ES
dc.subject.meshImmune Evasiones_ES
dc.subject.meshTumor Microenvironmentes_ES
dc.titleThe Peptidoglycan Recognition Protein 1 confers immune evasive properties on pancreatic cancer stem cells.es_ES
dc.typeresearch articlees_ES
dc.type.hasVersionVoRes_ES
dspace.entity.typePublication
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Grupos de investigación
i+12 - Instituto de Investigación Hospital 12 de Octubre (Madrid)
IDIBELL - Instituto de Investigación Biomédica de Bellvitge (Cataluña)
IRYCIS - Instituto Ramón y Cajal de Investigación Sanitaria (Madrid)