INVESTIGADORES
ZWIRNER Norberto Walter
congresos y reuniones científicas
Título:
Tumor-induced IL-18 promotes PD-L1 expression on human NK cells
Autor/es:
SIERRA, JESSICA MARIEL; RAFFO IRAOLAGOITÍA, XIMENA LUCÍA; NÚÑEZ, SOL YANEL; ZIBLAT, ANDREA; TORRES, NICOLÁS IGNACIO; SECCHIARI, FLORENCIA; DOMAICA, CAROLINA INÉS; ZWIRNER, NORBERTO WALTER; FUERTES, MERCEDES BEATRIZ
Lugar:
Mar del Plata
Reunión:
Congreso; 64a Reunión Anual de la Sociedad Argentina de Inmunología; 2016
Institución organizadora:
Sociedad Argentina de Inmunología
Resumen:
Natural killer (NK) cells are important mediators in the elimination oftumor and virus-infected cells, however, novel reports show a regulatory rolefor NK cells in different models of autoimmunity and viral infections. We haveshown that NK cells from tumor bearing mice express the inhibitory moleculePD-L1 and are able to control CD8+ T cell priming to tumor antigensin vivo. Moreover, in human NK cells, direct tumor recognition through NKG2Dinduced PD-L1 up-regulation, which was further enhanced in the presence of peripheralblood mononuclear cells (PBMCs). Therefore, the objective of this work was to elucidate the mechanisms involved inPBMC-mediated induction of PD-L1 expression on human NK cells after tumorrecognition. To this end, PBMCs were cultured with K562 tumor cells and theconditioned medium (CM) obtained was used to stimulate NK cells. The CM wasable to induce PD-L1 expression on NK cells (CD3-CD56+) asassessed by flow cytometry, suggesting the involvement of soluble factors. Aimingto identify these factors, PBMCs or isolated NK cells were stimulated withdifferent doses of NK cell-activating recombinant cytokines (IL-12, IL-15 orIL-18) or cultured with K562 cells in the absence or in the presence ofblocking antibodies to IL-12, IL-15 and/or IL-18. We found that IL-12 was notable to modulate PD-L1 expression. Although PD-L1 expression was induced byIL-15 on NK cells (within PBMCs, p<0.01 or isolated, p<0.01), IL-15blockade during the co-culture of PBMCs with K562 cells did not modulate PD-L1expression, suggesting that it is not involved in tumor-induced PD-L1 up-regulation.Finally, we found that PD-L1 expression on NK cells within PBMCs was induced byIL-18 (p<0.0001); moreover, IL-18 blockade in co-cultures of PBMCs with K562cells abrogated tumor-induced PD-L1 up-regulation (p<0.05). Our resultsdemonstrate that IL-18 produced by PBMCs after tumor recognition is able toup-regulate PD-L1 expression on human NK cells.