NK CELLS LIMIT SECONDARY TUMOR CONTROL THROUGH PD-1/PD-L1 INTERACTIONS WITH DENDRITIC CELLS

RAFFO IRAOLAGOITIA XIMENA LUCÍA; ARAYA ROMINA ELIZABETH; SIERRA JESSICA MARIEL; SPALLANZANI RAUL GERMAN; TORRES NICOLÁS IGNACIO; ZIBLAT ANDREA; NUÑEZ SOL YANEL; DOMAICA CAROLINA INÉS; ZWIRNER NORBERTO WALTER; FUERTES MERCEDES BEATRIZ

Ciudad Autónoma de Buenos Aires

Congreso; LXIII Argentinean Immunology Society Meeting; 2015

Sociedad Argentina de Inmunología

Background. Despite the conventional immunostimulatory functions of Natural Killer (NK) cells, recent findings revealed a regulatory role of NK cells in certain experimental and clinical settings. We have previously reported that NK cells can limit cross-priming of anti-tumor CD8 T cells leading to reduced memory responses. Therefore, the aim of this work was to study the consequences and the mechanisms underlying this NK cell-dependent regulatory circuit. Methods and Results. NK cell-depleted and control mice were subcutaneously injected with immunogenic MC57.SIY tumor cells and three months later, mice were re-challenged with B16.SIY cells and tumor growth was assessed. We observed that mice primed with MC57.SIY cells in the absence of NK cells exhibited increased frequency of tumor rejection and delayed tumor growth. According to our previous finding that NK cells up-regulate PD-L1 expression after tumor challenge, we found by flow cytometry an increased frequency of PD-1 dendritic cells (DC), but not CD8 T cells, in tumor-draining lymph nodes from NK cell-depleted mice upon MC57.SIY challenge. Finally, we showed by flow cytometry that sorted intra-tumoral NK (TINK) cells from MC57.SIY challenged mice, but not resting NK cells sorted from spleen nor TINK cells in the presence of anti-PD-L1 blocking antibody, inhibited in vitro DC maturation with LPS and R848. Conclusions. Collectively, our results suggest a model where tumor-primed NK cells controlDC activation through PD-L1/PD-1 interactions, which in turn limit CD8 T cell priming and memory responses, resulting in a reduced ability to control tumor growth upon a secondary challenge.