Tumor-experienced human NK cells express PD-L1 and display immunoregulatory functions

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

Washington

Congreso; ?Immunology 2017? (104th Congress of the American Association of Immunologists); 2017

American Association of Immunologists

While NK cells play a key role in the elimination of infected cells and tumors, regulatory functions of NK cells are emerging in several models of viral infections and autoimmunity. In the tumor context, we have recently described an immunoregulatory population of PD-L1-expressing NK cells arising in tumor-bearing mice that inhibits CD8+ T cells priming. Since little is known about the expression of PD-L1 on human NK cells, the aim of this work was to study its expression on human NK cells after tumor recognition and the underlying mechanisms. After culture of human PBMCs from healthy donors with K562 tumor cells, PD-L1 expression was induced on NK cells. Transwell and receptor blockade experiments showed a dependence on cell-to-cell contact that involved NKG2D engagement. PD-L1 expression on isolated NK cells stimulated with K562 tumor cells could be further increased by soluble factors derived from tumor-stimulated PBMCs or by the addition of monocytes. Neutralization of different cytokines identified IL-18 as the main factor responsible for PD-L1 up-regulation, which can be produced by monocytes. These PD-L1hi NK cells were immunoregulatory, as they inhibited DC maturation in vitro. This population may be clinically relevant, as we detected PD-L1hi NK cells in the tumor microenvironment and in peripheral blood of human patients with kidney cancer, making PD-L1 expression on NK cells an attractive candidate as prognostic/diagnostic biomarker. Our results indicate that PD-L1 is expressed in tumor-experienced human NK cells which subsequently acquire immunoregulatory functions. Thus, rational manipulation of these regulatory cells could lead to improved anti-tumor immunity in vivo.