期刊
CANCER RESEARCH
卷 79, 期 21, 页码 5482-5489出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-19-1302
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资金
- US NIH [R01CA160331, R01CA163377, R01CA202919, R01CA239128, P50CA228991]
- US Department of Defense [OC150446, OC180109]
- Cancer Centre Support Grant [CA010815]
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.
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