Epigenetic priming of both tumor and NK cells augments antibody-dependent cellular cytotoxicity elicited by the anti-PD-L1 antibody avelumab against multiple carcinoma cell types.
Epigenetic priming of both tumor and NK cells augments antibody-dependent cellular cytotoxicity elicited by the anti-PD-L1 antibody avelumab against multiple carcinoma cell types.
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DOI：
10.1080/2162402x.2018.1466018
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发表时间：
2018
期刊：
影响因子：
7.2
通讯作者：
Gameiro SR
中科院分区：
文献类型：
--
作者：
Hicks KC;Fantini M;Donahue RN;Schwab A;Knudson KM;Tritsch SR;Jochems C;Clavijo PE;Allen CT;Hodge JW;Tsang KY;Schlom J;Gameiro SR
靶向PD-1/PD-L1轴的检查点抑制剂是有希望的免疫疗法，显示出对多种肿瘤类型的客观反应，但这些药物未能使大多数癌症患者受益。这突出了开发有效的治疗策略以增加对PD-1/PD-L1阻断的反应的需要。组蛋白去乙酰化酶（HDAC）抑制剂与免疫疗法的组合提供了抗肿瘤作用的初步证据。我们在此研究了自然杀伤（NK）细胞和/或肿瘤细胞暴露于两种不同类别的HDAC抑制剂是否会增加（a）NK细胞介导的直接肿瘤细胞杀伤和/或（B）使用avelumab（一种靶向PD-L1的全人源IgG 1单克隆抗体）的抗体依赖性细胞毒性（ADCC）。用临床相关剂量的泛HDAC抑制剂伏立诺他或I类HDAC抑制剂恩替诺特处理多种人类癌细胞显著增强了多种NK配体和死亡受体的表达，导致增强的NK细胞活化介导的裂解。此外，HDAC抑制增强了体外和癌异种移植物中的肿瘤细胞PD-L1表达。这些数据表明，用两种不同类别的HDAC抑制剂处理多种癌细胞导致增强的NK细胞肿瘤细胞溶解和avelumab介导的ADCC。此外，恩替司他治疗来自健康供体的NK细胞和来自癌症患者的PBMC诱导了活化的NK细胞表型，并提高了多种癌症类型的直接和ADCC介导的健康供体NK裂解。因此，这项研究扩展了机制，并为HDAC抑制剂与PD-1/PD-L1检查点阻断剂联合使用以增加患者对抗PD-1/PD-L1治疗的反应提供了依据。
Checkpoint inhibitors targeting the PD-1/PD-L1 axis are promising immunotherapies shown to elicit objective responses against multiple tumor types, yet these agents fail to benefit most patients with carcinomas. This highlights the need to develop effective therapeutic strategies to increase responses to PD-1/PD-L1 blockade. Histone deacetylase (HDAC) inhibitors in combination with immunotherapies have provided preliminary evidence of anti-tumor effects. We investigated here whether exposure of either natural killer (NK) cells and/or tumor cells to two different classes of HDAC inhibitors would augment (a) NK cell‒mediated direct tumor cell killing and/or (b) antibody-dependent cellular cytotoxicity (ADCC) using avelumab, a fully human IgG1 monoclonal antibody targeting PD-L1. Treatment of a diverse array of human carcinoma cells with a clinically relevant dose of either the pan-HDAC inhibitor vorinostat or the class I HDAC inhibitor entinostat significantly enhanced the expression of multiple NK ligands and death receptors resulting in enhanced NK cell‒mediated lysis. Moreover, HDAC inhibition enhanced tumor cell PD-L1 expression both in vitro and in carcinoma xenografts. These data demonstrate that treatment of a diverse array of carcinoma cells with two different classes of HDAC inhibitors results in enhanced NK cell tumor cell lysis and avelumab-mediated ADCC. Furthermore, entinostat treatment of NK cells from healthy donors and PBMCs from cancer patients induced an activated NK cell phenotype, and heightened direct and ADCC-mediated healthy donor NK lysis of multiple carcinoma types. This study thus extends the mechanism and provides a rationale for combining HDAC inhibitors with PD-1/PD-L1 checkpoint blockade to increase patient responses to anti-PD-1/PD-L1 therapies.