O7 - Cáncer

Impact of pancreatic cancer-derived extracellular vesicles on NK cell function: distinct immune modulation in localized vs. metastatic tumors

Ledesma, Martín M. ^1,2,3 - Soubeyran, Philippe ⁴ - Bonilla, Lucy E. ^1,2,5 - Pulido, Viviana ^2,5,6 - Mirakián, Nadia ⁶ - Gottardo, Florencia ^7,8,9 - Garona, Juán ^7,8,9 - García, María Noé ^5,6 - Grasso, Daniel ^6,10 - Chuluyán, Eduardo ^11,12 - Dusetti, Nelson ⁴ - Iovanna, Juan ⁴ - Papademetrio, Daniela L. ^1,2,5,13

1) Unidad de Conocimiento Traslacional, Hospital de Alta Complejidad del Bicentenario Esteban Echeverría, Monte Grande, Buenos Aires, Argentina
2) Centro de Investigaciones en Biomedicina traslacional CIBiMeT, CONICET - Hospital de Alta Complejidad del Bicentenario Esteban Echeverría, Monte Grande, Buenos Aires, Argentina
3) Centro de Excelencia en Medicina Traslacional CEMET, Hospital de Alta Complejidad El Cruce, Florencio Varela, Buenos Aires, Argentina
4) Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France
5) Cátedra de Inmunología, Departamento de Microbiología, Inmunología, Biotecnología y Genética, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, CABA, Argentina
6) Instituto de Estudios de la Inmunidad Humoral (IDEHU), UBA - CONICET, CABA, Argentina
7) Unidad de Investigaciones Biomédicas en Cáncer (IBioCAN, Unidad N°
6), Centro de Medicina Traslacional (CEMET), Hospital de Alta Complejidad en Red El Cruce “Dr. Néstor Carlos Kirchner” SAMIC, Buenos Aires, Argentina
8) Centro de Oncología Molecular y Traslacional (COMTra), Unidad de Oncología Traslacional, Universidad Nacional de Quilmes, Buenos Aires, Argentina
9) Consejo Nacional de Investigaciones Científicas (CONICET) 10) Cátedra de Fisiopatología, Departamento de Ciencias Biológicas, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, CABA, Argentina 11) Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Facultad de Medicina, Universidad de Buenos Aires-CONICET, CABA, Argentina 12) Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, CABA, Argentina 13) Laboratorio de la Red Franco-Argentina de Investigaciones en Páncreas, Unidad n°10, Centro de Medicina Traslacional (CEMET), Hospital de Alta Complejidad en Red El Cruce, Florencio Varela, Buenos Aires, Argentina
Contacto: danilpapa@gmail.com

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers due to its aggressive nature and immune evasion mechanisms, particularly involving natural killer (NK) cells. Understanding how tumor-derived extracellular vesicles (EVs) modulate NK cell function is crucial for developing novel therapeutic strategies. We analyzed the interactome between EV proteins from secretomes of primary PDAC cultures—localized (loc) (n=14) and metastatic (met) (n=7)—and NK cells from the tumor microenvironment (TME) and adjacent (ADJ) non-tumor tissue. EV proteomes were in-silico filtered for pancreatic EV (Exocarta) associated plasma membrane proteins. NK cell transcriptomes were obtained from single-cell RNA-seq data (GSE212966), selecting NK cells and membrane-associated genes. Protein-protein interactions with high-confidence physical evidence were retrieved from STRING v11.5 and visualized in Cytoscape. Key network nodes were identified using CytoHubba, classifying hubs into local, bridge, and global influencers.
Considering loc-EVs interacting with TME-NK, the key network nodes were endosomal ESCRT components, indicating modulation of receptor trafficking (such as CD16 and NKG2D) and a reduction in cytotoxic capacity. Signaling hubs included IL2RG and NF-κB inhibitors, suggesting suppression of activation pathways. When interacting with ADJ-NK cells, loc-EVs affect proteins related to the cytoskeleton and cell adhesion (RHOA/ROCK pathway), which may impair NK cell movement and the formation of immune synapses. 
When analyzing met-EVs, the key network nodes are adhesion molecules (integrins ITGB1/ITGA4) and actin regulators (CDC42), along with ribosomal proteins, indicating altered TME-NK cell adhesion and protein synthesis. ADJ-NK cells share these hubs with added involvement of PI3K signaling (PIK3R1), linked to NK cell survival but remain unfunctional in suppression.
Overall, loc-EVs modulate NK cells through vesicular trafficking and overall signaling inhibition, while met-EVs focus on adhesion, cytoskeletal remodeling, and translational control. NK cells in the TME are more affected by activation suppression, whereas those in ADJ-tissue experience altered motility and interaction capacity. These different mechanisms may highlight distinct immune evasion strategies in PDAC progression and could serve as targets for immunomodulatory therapies

Palabras clave: PANCREATIC DUCTAL ADENOCARCINOMA - NATURAL KILLER CELLS - EXTRACELLULAR VESICLES - TUMOR MICROENVIRONMENT - IMMUNE EVASION