A selective HDAC8 inhibitor potentiates antitumor immunity and efficacy of immune checkpoint blockade in hepatocellular carcinoma

Abstract

Insufficient T cell infiltration into noninflamed tumors, such as hepatocellular carcinoma (HCC), restricts the effectiveness of immune-checkpoint blockade (ICB) for a subset of patients. Epigenetic therapy provides further opportunities to rewire cancer-associated transcriptional programs, but whether and how selective epigenetic inhibition counteracts the immune-excluded phenotype remain incompletely defined. Here, we showed that pharmacological inhibition of histone deacetylase 8 (HDAC8), a histone H3 lysine 27 (H3K27)–specific isozyme overexpressed in a variety of human cancers, thwarts HCC tumorigenicity in a T cell–dependent manner. The tumor-suppressive effect of selective HDAC8 inhibition was abrogated by CD8+ T cell depletion or regulatory T cell adoptive transfer. Chromatin profiling of human HDAC8-expressing HCCs revealed genome-wide H3K27 deacetylation in 1251 silenced enhancer-target gene pairs that are enriched in metabolic and immune regulators. Mechanistically, down-regulation of HDAC8 increased global and enhancer acetylation of H3K27 to reactivate production of T cell–trafficking chemokines by HCC cells, thus relieving T cell exclusion in both immunodeficient and humanized mouse models. In an HCC preclinical model, selective HDAC8 inhibition increased tumor-infiltrating CD8+ T cells and potentiated eradication of established hepatomas by anti–PD-L1 therapy without evidence of toxicity. Mice treated with HDAC8 and PD-L1 coblockade were protected against subsequent tumor rechallenge as a result of the induction of memory T cells and remained tumor-free for greater than 15 months. Collectively, our study demonstrates that selective HDAC8 inhibition elicits effective and durable responses to ICB by co-opting adaptive immunity through enhancer reprogramming.

Construction of a Ferroptosis-Related Nine-lncRNA Signature for Predicting Prognosis and Immune Response in Hepatocellular Carcinoma

“…These observations implied that the infiltration of these immune cell subtypes might exert an important influence on the prognosis of HCC patients. Given the clinical importance of therapeutic strategies based on immune checkpoint blockade in HCC (32,33), we then explore the association between the risk score and several immune checkpoints, such as PD1, PDL1, CTLA4, VSIR, and B7H3. As shown in Figure 7F, the heat map showed the positive relations between risk score and these immune checkpoints.…”

Lysine Acetylation/Deacetylation Modification of Immune-Related Molecules in Cancer Immunotherapy

“…For instance, HDACi in combination with anti-PD-1 or anti-CTLA-4 antibodies were found to promote the production of granase B in activated CD8 + T responder cells, significantly improving the infiltration and function of innate immune cells and enhancing adaptive immune response. Using a hepatocellular carcinoma preclinical model, selective HDAC8 inhibition was found to exert effective responses to anti-PD-L1 treatment by reactivating the production of T cell-trafficking chemokines ( 107 ). CG-745, a member of HDACi, has been validated to modulate the immune microenvironment and enhance the therapeutic effect of anti-PD-1 ICIs, which indicates the effectiveness of the combined application of HDACi and ICIs ( 108 ).…”

Acetylation in Tumor Immune Evasion Regulation

“…et al, 2018 ). However, opposite studies have shown that HDAC8 inhibition increases the expression of NKG2D ligand in glioma cells which enhanced the recognition ability and cytotoxicity of NK cells, and activates immune cells in hepatocellular carcinoma resulting in an effective and lasting response to ICB ( Yang W. et al, 2021 ; Mormino et al, 2021 ). On the contrary, HDAC9 and HDAC10 are opposite to HDAC8 in up-regulating PD-L1.…”