NKG2D ENGAGEMENT AND IFN-γ INDUCE THE UP-REGULATION OF PD-L1 ON HUMAN NK CELLS UPON TUMOR RECOGNITION

SIERRA JM; IRAOLAGOITIA XL; ZIBLAT A; TORRES NI; NUÑEZ SY; ARAYA RE; DOMAICA CI; FUERTES MB; ZWIRNER NW

Buenos Aires

Congreso; IV LASID Meeting; LXIII Argentinean Immunology Society Meeting and II French Argentinean Immunology Meeting; 2015

SAI

Background: Despite the classical function of natural killer (NK) cells in the elimination of tumor and virus-infected cells, novel reports show a regulatory role for NK cells in different models of autoimmunity and viral infections. Moreover, we have recently shown that murine NK cells can control CD8+ T cell priming to tumor antigens in vivo, through regulation of DC maturation in a mechanism involving PD-1/PD-L1 interactions. The objective of the present work was to study PD-L1 up-regulation in human NK cells upon tumor recognition and the underlying mechanisms. Methods: Peripheral blood mononuclear cells (PBMC) or isolated NK cells from healthy human donors were stimulated with IFN- or co-cultured with K562 target tumor cells in the presence or in the absence of anti-NKG2D or anti-IFN- receptor blocking antibodies or using a transwell insert, and PD-L1 expression on NK cells (CD3-CD56+ cells) was evaluated by flow cytometry. Alternatively, PBMCs were co-cultured with different cell lines (ECC-1, PC3, MDA-MB-453, CACO2, K562 and HeLa) and PD-L1 expression was analyzed on NK cells. Results: PD-L1 expression was up-regulated on NK cells after 48 h of stimulation with K562 cells. Transwell and NKG2D blockade experiments showed a dependence on direct cell-to-cell contact through NKG2D engagement. Also, IFN- alone was not sufficient but was partially required to induce PD-L1 expression. Moreover, PD-L1 up-regulation on NK cells observed in response to a broader panel of human cell lines suggests that this constitutes a generalized phenomenon.Conclusions: Direct tumor recognition through NKG2D induces PD-L1 up-regulation on human NK cells.