American Association for Cancer Research
21598290cd181259-sup-211076_3_supp_5609033_ptlzks.pdf (2.19 MB)

Supplementary Data from The Mechanism of Anti–PD-L1 Antibody Efficacy against PD-L1–Negative Tumors Identifies NK Cells Expressing PD-L1 as a Cytolytic Effector

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journal contribution
posted on 2023-04-03, 21:42 authored by Wenjuan Dong, Xiaojin Wu, Shoubao Ma, Yufeng Wang, Ansel P. Nalin, Zheng Zhu, Jianying Zhang, Don M. Benson, Kai He, Michael A. Caligiuri, Jianhua Yu

Supplementary figures and figure legends as well as supplementary methods and materials



Leukemia and Lymphoma Society

American Cancer Society Scholar Award



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. 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