Blockade of PD-L1 expression on tumor cells via anti-PD-L1 monoclonal antibody (mAb) has shown great promise for successful cancer treatment by overcoming T-cell exhaustion; however, the function of PD-L1 on natural killer (NK) cells and the effects of anti-PD-L1 mAb on PD-L1⁺ NK cells remain unknown. Moreover, patients with PD-L1 ^- tumors can respond favorably to anti-PD-L1 mAb therapy for unclear reasons. Here, we show that some tumors can induce PD-L1 on NK cells via AKT signaling, resulting in enhanced NK-cell function and preventing cell exhaustion. Anti-PD-L1 mAb directly acts on PD-L1⁺ NK cells against PD-L1 ^- tumors via a p38 pathway. Combination therapy with anti-PD-L1 mAb and NK cell-activating cytokines significantly improves the therapeutic efficacy of human NK cells against PD-L1 ^- human leukemia when compared with monotherapy. Our discovery of a PD-1-independent mechanism of antitumor efficacy via the activation of PD-L1⁺ NK cells with anti-PD-L1 mAb offers new insights into NK-cell activation and provides a potential explanation as to why some patients lacking PD-L1 expression on tumor cells still respond to anti-PD-L1 mAb therapy. SIGNIFICANCE: Targeting PD-L1 expressed on PD-L1⁺ tumors with anti-PD-L1 mAb successfully overcomes T-cell exhaustion to control cancer, yet patients with PD-L1 ^- tumors can respond to anti-PD-L1 mAb. Here, we show that anti-PD-L1 mAb activates PD-L1⁺ NK cells to control growth of PD-L1 ^- tumors in vivo, and does so independent of PD-1.This article is highlighted in the In This Issue feature, p. 1325.

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