| First Author | Dong W | Year | 2019 |
| Journal | Cancer Discov | Volume | 9 |
| Issue | 10 | Pages | 1422-1437 |
| PubMed ID | 31340937 | Mgi Jnum | J:279992 |
| Mgi Id | MGI:6363878 | Doi | 10.1158/2159-8290.CD-18-1259 |
| Citation | Dong W, et al. (2019) The Mechanism of Anti-PD-L1 Antibody Efficacy against PD-L1-Negative Tumors Identifies NK Cells Expressing PD-L1 as a Cytolytic Effector. Cancer Discov 9(10):1422-1437 |
| abstractText | 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. |
