Monocyte-derived IL-18 enhance PD-L1 expression on tumor-experienced human NK cells

SIERRA, JESSICA MARIEL; NÚÑEZ, SOL YANEL; SECCHIARI, FLORENCIA; ZIBLAT, ANDREA; REGGE, MARÍA VICTORIA; FRIEDRICH ADRIAN; DOMAICA, CAROLINA INÉS; ZWIRNER, NORBERTO WALTER; FUERTES, MERCEDES BEATRIZ

Mar del Plata

Congreso; Reunión anual de la Sociedad Argentina de Inmunología; 2018

SAIC-SAI-SAFIS

Natural killer (NK) cells play an important role in the elimination of tumor andvirus-infected cells, however, recently evidence of a regulatory role is emergingin different models of autoimmunity, transplants and viral infections. In the tumorcontext, we have demonstrated that NK cells from tumor bearing mice showedan up-regulated expression of the inhibitory molecule PD-L1 and restrict CD8 + Tcell priming. Moreover, in human NK cells, direct tumor recognition throughNKG2D receptor induced the expression of PD-L1, which was further up-regulated in the presence of peripheral blood mononuclear cells (PBMCs)through IL-18. However, the underlying mechanisms that control theseinteractions are unknown. Thus, the aim of this work was to identify the IL-18-producing cell population and the signals and cells involved in its induction,which results in PD-L1 expression on human NK cells. To distinguish betweenNK cell-derived factors versus tumor cell-derived factors, we generatedconditioned medium (CM) from NK cells cultured with K562 tumor cells and CMfrom serum-deprived apoptotic K562 cells. Then, PBMCs were stimulated withthese CM or with K562 cells in the absence or in the presence of an IFN-gneutralizing antibody. K562 cells and both CM induced IL-18 secretion byPBMCs, measured by ELISA, which was partially reduced by IFN-g blockade.Next, to identify the IL-18-producing population, we cultured NK cells with K562cells, with or without syngeneic monocytes. The addition of monocytes resultedin a higher IL-18 secretion evaluated by ELISA (p