Dataset Information

HDAC6 inhibitor ACY-1215 enhances STAT1 acetylation to block PD-L1 for colorectal cancer immunotherapy.

ABSTRACT: The search for effective combination therapy with immune checkpoint inhibitors (ICI) has become important for cancer patients who do not respond to the ICI well. Histone deacetylases (HDACs) inhibitors have attracted wide attention as anti-tumor agents. ACY-1215 is a selective inhibitor of HDAC6, which can inhibit the growth of a variety of tumor. We previously revealed that HDAC family is highly expressed in colorectal cancer specimens and mouse models. In this study, ACY-1215 was combined with anti-PD1 to treat tumor-bearing mice associated with colorectal cancer. ACY-1215 combined with anti-PD1 effectively inhibited the colorectal tumor growth. The expression of PD-L1 in tumor of mice were inhibited by ACY-1215 and anti-PD1 combination treatment, whereas some biomarkers reflecting T cell activation were upregulated. In a co-culture system of T cells and tumor cells, ACY-1215 helped T cells to kill tumor cells. Mechanically, HDAC6 enhanced the acetylation of STAT1 and inhibited the phosphorylation of STAT1, thus preventing STAT1 from entering the nucleus to activate PD-L1 transcription. This study reveals a novel regulatory mechanism of HDAC6 on non-histone substrates, especially on protein acetylation. HDAC6 inhibitors may be of great significance in tumor immunotherapy and related combination strategies.

SUBMITTER: Wen Y

PROVIDER: S-EPMC10794344 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

HDAC6 inhibitor ACY-1215 enhances STAT1 acetylation to block PD-L1 for colorectal cancer immunotherapy.

Wen Yuqing Y Ye Shuyu S Li Zhengshuo Z Zhang Xiaoyue X Liu Can C Wu Yangge Y Zheng Run R Xu Chenxiao C Tian Junrui J Shu Lanjun L Yan Qun Q Ai Feiyan F Ma Jian J

Cancer immunology, immunotherapy : CII 20240117 1

The search for effective combination therapy with immune checkpoint inhibitors (ICI) has become important for cancer patients who do not respond to the ICI well. Histone deacetylases (HDACs) inhibitors have attracted wide attention as anti-tumor agents. ACY-1215 is a selective inhibitor of HDAC6, which can inhibit the growth of a variety of tumor. We previously revealed that HDAC family is highly expressed in colorectal cancer specimens and mouse models. In this study, ACY-1215 was combined with ...[more]

PMID: 38231305

Similar Datasets

Project description:Lessons learnedOral selective HDAC6 inhibitors could allow for decreased toxicity compared to pan-class inhibitors, and increased ease of use. ACY-1215 is well tolerated and led to disease stabilization in 50% of patients treated on a twice-daily dosing schedule. Rational drug combinations with ACY-1215 improve efficacy in patients with lymphoma. Biomarkers such as XBP-1 level or HDAC6-score may improve patient selection.BackgroundACY-1215, ricolinostat, is an oral, first-in-class isoform-selective HDAC6 inhibitor. HDAC6 is a class IIb deacetylase and plays a critical role in protein homeostasis via the unfolded protein response (UPR). Lymphocytes generate a large repertoire of antibodies and depend on an activated UPR to maintain proteostasis. Lymphomas utilize this biology to evade programmed cell death. In preclinical models of lymphoma, ACY-1215 disrupted proteostasis, triggering apoptosis.MethodsWe translated these findings into a multi-institution, open-label, dose-escalation phase Ib/II study aimed to determine the safety and efficacy in patients with relapsed and refractory lymphoma.ResultsTwenty-one patients with heavily pretreated lymphoma were accrued. Patients in the phase Ib portion were enrolled on one of two dose cohorts [Arm A: 160 mg daily (n = 3) or Arm B: 160 mg twice daily (n = 10)]. ACY-1215 was well tolerated. There were no dose limiting toxicities. Most adverse events were grade 1-2, including diarrhea (57%), nausea (57%), and fatigue (43%). Grade 3-4 toxicities were rare and included anemia (9.5%) and hypercalcemia (9.5%). An additional 8 patients were enrolled on the phase II portion, at 160 mg twice daily. Sixteen patients were evaluable for response. ACY-1215 did not result in any complete or partial responses in patients treated. Eight patients had stable disease (50%) lasting a median duration of 4.5 months, all of whom were treated twice daily. Disease progressed in eight patients (50%) at cycle 2. Five patients were not evaluable due to disease progression prior to cycle 2. The median PFS was 56 days.ConclusionACY-1215 is an oral selective HDAC6 inhibitor that was safe in patients with relapsed and refractory lymphoid malignancies and led to disease stabilization in half of the evaluable patients.

Dataset Information

HDAC6 inhibitor ACY-1215 enhances STAT1 acetylation to block PD-L1 for colorectal cancer immunotherapy.

Publications

HDAC6 inhibitor ACY-1215 enhances STAT1 acetylation to block PD-L1 for colorectal cancer immunotherapy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets