HDAC6 Inhibition Synergizes with Anti-PD-L1 Therapy in ARID1A-Inactivated Ovarian Cancer.

Abstract

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 ARID1Aflox/flox/PIK3CAH1047R OCCC mice treated with the HDAC6 inhibitor ACY1215 and anti-PD-L1 immune checkpoint blockade as a result of activation and increased presence of IFNγ-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.See related commentary by Prokunina-Olsson, p. 5476.

• Authors: Takeshi Fukumoto, Nail Fatkhutdinov, Joseph A Zundell, Evgenii N Tcyganov, Timothy Nacarelli, Sergey Karakashev, Shuai Wu, Qin Liu, Dmitry I Gabrilovich, Rugang Zhang
• Journal: Cancer research (Cancer Res) Vol. 79 Issue 21 Pg. 5482-5489 (11 01 2019) ISSN: 1538-7445 [Electronic] United States
• PMID: 31311810 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Comment)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• ARID1A protein, human
• Arid1a protein, mouse
• B7-H1 Antigen
• DNA-Binding Proteins
• Nuclear Proteins
• Transcription Factors
• HDAC6 protein, human
• Histone Deacetylase 6

Topics

• Adenocarcinoma, Clear Cell
• Animals
• B7-H1 Antigen
• CD8-Positive T-Lymphocytes
• DNA-Binding Proteins
• Female
• Histone Deacetylase 6
• Humans
• Mice
• Nuclear Proteins
• Ovarian Neoplasms
• Transcription Factors
• Tumor Microenvironment