For hepatocellular carcinoma (HCC), durable responses and improved survivals have been
reported in clinical trials on immune checkpoint inhibitor (ICI)-based treatment. However,
resistance to ICI is increasingly encountered in clinical practice in HCC patients.
Various approaches are currently evaluated in clinical setting to tackle acquired resistance
during treatment of ICIs in HCC.
Our group has a track record of studying the role of histone deacetylases (HDACs) in
mediating resistance to ICI in HCC. First, based on single-cell sequencing data of serial
biopsy of tumor in our phase II clinical trial on pembrolizumab in HCC (NCT03419481), the
investigators reveal an upregulation of class 1 HDAC in patients with acquired resistance to
pembrolizumab, which was associated with reduced lymphoid/myeloid cellular ratio in the
tumor. Further, the investigators showed that HDAC8, a class 1 HDAC, could diminish the
efficacy of anti-programmed cell death (ligand)-1 (PD[L]-1) by the mechanism of T-cell
exclusion from the tumor environment (SciTranl Med. 2021;13:online). Finally, the
investigators combine CXD101, a potent selective class I HDAC inhibitor, with anti-PD(L)-1 in
orthotopic immunocompetent HCC mouse model with resistance to anti-PD(L)-1 treatment and find
that the combination regimen could reverse the resistance phenotype and significantly improve
survivals of mice than either CXD101 or anti-PD(L)-1 alone.