Tumor-experienced NK cells inhibit T cell proliferation and activation through PD-L1

SIERRA, JESSICA MARIEL; ZIBLAT, ANDREA; REGGE, MARÍA VICTORIA; SECCHIARI, FLORENCIA; FUERTES, MERCEDES BEATRIZ; TORRES, NICOLÁS IGNACIO; ZWIRNER, NORBERTO WALTER; RAFFO IRAOLAGOITÍA, XIMENA LUCÍA; NÚÑEZ, SOL YANEL; DOMAICA, CAROLINA INÉS

Chicago

Congreso; AACR Annual Meeting 2018; 2018

American Association of Cancer Research

Natural killer (NK) cells play an important role in the elimination of tumor and virus-infected cells, however, recently evidence of a regulatory role is emerging in different models of autoimmunity, transplants and viral infections. In the tumor context, we have demonstrated that NK cells from tumor bearing mice showed an up-regulated expression of the inhibitory molecule PD-L1 and restrict CD8+ T cell priming. Moreover, in human NK cells, direct tumor recognition through NKG2D 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 these interactions 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 between NK cell-derived factors versus tumor cell-derived factors, we generated conditioned medium (CM) from NK cells cultured with K562 tumor cells and CM from serum-deprived apoptotic K562 cells. Then, PBMCs were stimulated with these CM or with K562 cells in the absence or in the presence of an IFN-g neutralizing antibody. K562 cells and both CM induced IL-18 secretion by PBMCs, measured by ELISA, which was partially reduced by IFN-g blockade. Next, to identify the IL-18-producing population, we cultured NK cells with K562 cells, with or without syngeneic monocytes. The addition of monocytes resulted in a higher IL-18 secretion evaluated by ELISA (p