PD-L1 blockade enhances anti-tumor efficacy of NK cells.
PD-L1 blockade enhances anti-tumor efficacy of NK cells.
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DOI：
10.1080/2162402x.2018.1509819
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发表时间：
2018
期刊：
影响因子：
7.2
通讯作者：
Copik AJ
中科院分区：
文献类型：
--
作者：
Oyer JL;Gitto SB;Altomare DA;Copik AJ
抗PD-1/抗PD-L1疗法在癌症治疗中已显示出成功，但缓解仅限于约15%的淋巴细胞浸润、PD-L1阳性肿瘤患者。因此，增加PD-L1表达和肿瘤浸润的策略应该使更多的患者有资格接受PD-1/PD-L1阻断治疗，从而改善总体结局。肿瘤上的PD-L1表达由IFNγ诱导，IFN γ是NK细胞分泌的一种细胞因子。因此，我们在卵巢癌模型中测试了PM21颗粒扩增的NK细胞（PM21-NK细胞）是否诱导肿瘤上的PD-L1表达，以及抗PD-L1治疗是否增强NK细胞抗肿瘤功效。研究表明，PM21-NK细胞分泌大量IFNγ，过继转移的PM21-NK细胞在体内诱导SKOV-3细胞上的PD-L1表达。SKOV-3细胞上PD-L1表达的诱导与腹腔和肿瘤内存在调节性T细胞（TCLs）相一致。在体外实验中，抗PD-L1处理对主要PD-1阴性PM21-NK细胞响应PD-L1+靶标的细胞毒性或细胞因子分泌无直接影响。然而，当与抗PD-L1组合时，在体内观察到NK细胞抗肿瘤功效的显著改善。PD-L1阻断还导致体内NK细胞持久性增加和细胞毒性表型保留。这些结果支持抗PD-L1与NK细胞治疗联合使用，无论初始肿瘤PD-L1状态如何，并表明NK细胞治疗可能会增强抗PD-L1治疗的适用性。
Anti-PD-1/anti-PD-L1 therapies have shown success in cancer treatment but responses are limited to ~ 15% of patients with lymphocyte infiltrated, PD-L1 positive tumors. Hence, strategies that increase PD-L1 expression and tumor infiltration should make more patients eligible for PD-1/PD-L1 blockade therapy, thus improving overall outcomes. PD-L1 expression on tumors is induced by IFNγ, a cytokine secreted by NK cells. Therefore, we tested if PM21-particle expanded NK cells (PM21-NK cells) induced expression of PD-L1 on tumors and if anti-PD-L1 treatment enhanced NK cell anti-tumor efficacy in an ovarian cancer model. Studies here showed that PM21-NK cells secrete high amounts of IFNγ and that adoptively transferred PM21-NK cells induce PD-L1 expression on SKOV-3 cells in vivo. The induction of PD-L1 expression on SKOV-3 cells coincided with the presence of regulatory T cells (Tregs) in the abdominal cavity and within tumors. In in vitro experiments, anti-PD-L1 treatment had no direct effect on cytotoxicity or cytokine secretion by predominantly PD-1 negative PM21-NK cells in response to PD-L1+ targets. However, significant improvement of NK cell anti-tumor efficacy was observed in vivo when combined with anti-PD-L1. PD-L1 blockade also resulted in increased in vivo NK cell persistence and retention of their cytotoxic phenotype. These results support the use of anti-PD-L1 in combination with NK cell therapy regardless of initial tumor PD-L1 status and indicate that NK cell therapy would likely augment the applicability of anti-PD-L1 treatment.