Editors' ChoiceCancer

NK cells: A new player for the defense

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Science Translational Medicine  13 Jul 2016:
Vol. 8, Issue 347, pp. 347ec111
DOI: 10.1126/scitranslmed.aah3545

Natural killer (NK) cells—innate immune cells known for their ability to target infected and transformed cells—have recently been reported to also control early-stage antiviral immune responses in lymph nodes, leading to reduced cytotoxic T cell responses and viral persistence, but also decreased autoimmunity. Mechanisms that tune immune responses regulate the balance between antiviral responses and tissue destruction, and many of these have emerged as extremely successful targets for clinical tumor immunotherapy—for example, programmed death ligand 1 (PD-L1), an inhibitor of antitumor response. In this work, Iraolagoitia et al. examined the effect of NK cells on the formation of spontaneous antitumor immunity. The authors found that, in addition to their established cytotoxic role, NK cells inhibit the priming of antitumor immune responses and as such might be a clinically relevant target.

The authors use an immunogenic fibrosarcoma model to demonstrate that NK cells, which are rapidly recruited to tumor-draining lymph nodes, limit T cell priming after tumor implantation, and inhibit dendritic cell maturation. When NK cells were depleted at the time of tumor challenge, protective immunity against a second challenge was boosted, consistent with the hypothesis that NK cells regulate dendritic cell function. Most tumor-infiltrating NK cells acquired a terminally differentiated phenotype, expressed high levels of PD-L1, and impaired dendritic cell maturation in vitro but had no direct effect on T cell proliferation. NK cell depletion resulted in an increase in PD-1+ dendritic cells, suggesting that PD-L1/PD-1 interactions with NK cells may eliminate dendritic cells as well as impair their maturation.

Efficacious tumor immunotherapy is dependent upon preexisting cytotoxic T cells. This work suggests that targeting NK cells in combination with or prior to immunotherapy may improve T cell priming to generate a circulating pool of T cells that control tumor growth and prevent recurrence. Additionally, the number of PD-L1–expressing hematopoietic cells rather than tumor cells predicts patients who respond to anti–PD-L1 therapy, indicating that NK cells, which express high levels of PD-L1, might contribute to the effectiveness of anti–PD-L1 therapy.

X. L. Raffo Iraolagoitia et al., NK cells restrain spontaneous antitumor CD8+ T cells priming through PD-1/PD-L1 interactions with dendritic cells. J. Immunol. 10.4049/jimmunol.1502291 (2016).[Abstract]

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