Tumor-induced IL-18 promotes PD-L1 expression on human NK cells

SIERRA JESSICA MARIEL; ZIBLAT ANDREA; DOMAICA CAROLINA INÉS; NUÑEZ SOL YANEL; SECCHIARI FLORENCIA; FUERTES MERCEDES BEATRIZ; RAFFO IRAOLAGOITIA XIMENA LUCÍA; TORRES NICOLÁS IGNACIO; ZWIRNER NORBERTO WALTER

Mar del Plata

Congreso; LXIV REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE INMUNOLOGÍA; 2016

Sociedad Argentina de Inmunología

Natural killer (NK) cells are important mediators in the elimination of tumor and virus-infected cells, however, novel reports show a regulatory role for NK cells in different models of autoimmunity and viral infections. We have shown that NK cells from tumor bearing mice express the inhibitory molecule PD-L1 and are able to control CD8+ T cell priming to tumor antigens in vivo. Moreover, in human NK cells, direct tumor recognition through NKG2D induced PD-L1 up-regulation, which was further enhanced in the presence of peripheral blood mononuclear cells (PBMCs). Therefore, the objective of this work was to elucidate the mechanisms involved in PBMC-mediated induction of PD-L1 expression on human NK cells after tumor recognition. To this end, PBMCs were cultured with K562 tumor cells and the conditioned medium (CM) obtained was used to stimulate NK cells. The CM was able to induce PD-L1 expression on NK cells (CD3-CD56+) as assessed by flow cytometry, suggesting the involvement of soluble factors. Aiming to identify these factors, PBMCs or isolated NK cells were stimulated with different doses of NK cell-activating recombinant cytokines (IL-12, IL-15 or IL-18) or cultured with K562 cells in the absence or in the presence of blocking antibodies to IL-12, IL-15 and/or IL-18. We found that IL-12 was not able to modulate PD-L1 expression. Although PD-L1 expression was induced by IL-15 on NK cells (within PBMCs, p