NK cells restrain spontaneous anti-tumor CD8+ T cell priming through PD-1/PD-L1 interactions with dendritic cells

RAFFO IRAOLAGOITÍA, XIMENA LUCÍA; ARAYA, ROMINA ELIZABETH; SIERRA, JESSICA MARIEL; GAJEWSKI, THOMAS; SPALLANZANI, RAÚL GERMÁN; ZIBLAT, ANDREA; NÚÑEZ, SOL YANEL; TORRES, NICOLÁS IGNACIO; ZWIRNER, NORBERTO WALTER; DOMAICA, CAROLINA INÉS; SECCHIARI, FLORENCIA; FUERTES, MERCEDES BEATRIZ

JOURNAL OF IMMUNOLOGY

AMER ASSOC IMMUNOLOGISTS

Lugar: Bethesda; Año: 2016 vol. 197

0022-1767

Despite the classical function of natural killer (NK) cells in the elimination of tumor and ofvirus-infected cells, evidence for a regulatory role for NK cells has been emerging indifferent models of autoimmunity, transplantation, and viral infections. However, this rolehas not been fully explored in the context of a growing tumor. Here we show that NK cellscan limit spontaneous cross-priming of tumor antigen-specific CD8+ T cells, leading toreduced memory responses. After challenge with MC57 cells transduced to express themodel antigen SIY (MC57.SIY), NK cell-depleted mice exhibited a significantly higherfrequency of SIY-specific CD8+T cells, with enhanced IFN-γ production and cytotoxiccapability. Depletion of NK cells resulted in a CD8+ T cell population skewed towards aneffector-memory T phenotype which was associated with enhanced recall responses after asecondary tumor challenge with B16.SIY cells. Dendritic cells (DC) from NK celldepletedtumor-bearing mice exhibited a more mature phenotype. Interestingly, tumorinfiltratingand tumor-draining lymph node NK cells displayed an up-regulated expressionof the inhibitory molecule PD-L1 that, through interaction with PD-1 expressed on DC,limited DC activation, explaining their reduced ability to induce tumor-specific CD8+ T cellpriming. Our results suggest that NK cells can, in certain contexts, have an inhibitoryeffect on anti-tumor immunity, a finding with implications for immunotherapy in the clinic.