HDAC6 Inhibition Synergizes with Anti-PD-L1 Therapy in ARID1A-Inactivated Ovarian Cancer
HDAC6 Inhibition Synergizes with Anti-PD-L1 Therapy in ARID1A-Inactivated Ovarian Cancer
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DOI：
10.1158/0008-5472.can-19-1302
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发表时间：
2019-11-01
期刊：
影响因子：
11.2
通讯作者：
Zhang, Rugang
中科院分区：
文献类型：
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作者：
Fukumoto, Takeshi;Fatkhutdinov, Nail;Zhang, Rugang
ARID1A编码SWI/SNF复合体的一个亚单位，是人类癌症中最频繁突变的表观遗传调节因子，在超过50%的卵巢透明细胞癌(OCCC)中发生突变，目前尚无有效的治疗方法。抑制组蛋白脱乙酰酶6(HDAC6)可抑制ARID1A突变肿瘤的生长，调节肿瘤免疫微环境。在这里，我们展示了在ARID1A失活的卵巢癌中，HDAC6的抑制与抗PD-L1免疫检查点阻断具有协同作用。ARID1A直接抑制编码PD-L1基因CD274的转录。在ARID1A(FLOX/FLOX)/PIK3CA(H1047R)OCCC小鼠中，使用HDAC6抑制剂ACY1215和抗PD-L1免疫检查点阻断后，由于激活和增加了干扰素-γ阳性CD8 T细胞的存在，观察到肿瘤负担减轻和存活率提高。我们证实，联合治疗以细胞毒性T细胞依赖的方式限制了肿瘤的进展，因为CD8(+)T细胞的耗尽消除了这些抗肿瘤作用。综上所述，这些发现表明，HDAC6抑制和免疫检查点阻断相结合代表了ARID1A突变癌症的一种潜在治疗策略。意义：这些发现为将表观遗传调节剂和现有免疫治疗干预措施结合起来对抗迄今抵抗检查点封锁的疾病作为单一疗法提供了机制基础。
ARID1A, encoding a subunit of the SWI/SNF complex, is the most frequently mutated epigenetic regulator in human cancers and is mutated in more than 50% of ovarian clear cell carcinomas (OCCC), a disease that currently has no effective therapy. Inhibition of histone deacetylase 6 (HDAC6) suppresses the growth of ARID1A-mutated tumors and modulates tumor immune microenvironment. Here, we show that inhibition of HDAC6 synergizes with anti-PD-L1 immune checkpoint blockade in ARID1A-inactivated ovarian cancer. ARID1A directly repressed transcription of CD274, the gene encoding PD-L1. Reduced tumor burden and improved survival were observed in ARID1A(flox/flox)/PIK3CA(H1047R) OCCC mice treated with the HDAC6 inhibitor ACY1215 and anti-PD-L1immune checkpoint blockade as a result of activation and increased presence of IFN gamma-positive CD8 T cells. We confirmed that the combined treatment limited tumor progression in a cytotoxic T-cell-dependent manner, as depletion of CD8(+) T cells abrogated these antitumor effects. Together, these findings indicate that combined HDAC6 inhibition and immune checkpoint blockade represents a potential treatment strategy for ARID1A-mutated cancers.Significance: These findings offer a mechanistic rationale for combining epigenetic modulators and existing immunotherapeutic interventions against a disease that has been so far resistant to checkpoint blockade as a monotherapy.