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A selective HDAC8 inhibitor potentiates antitumor immunity and efficacy of immune checkpoint blockade in hepatocellular carcinoma [RNA-seq]

ABSTRACT: A selective HDAC8 inhibitor potentiates antitumor immunity and efficacy of immune checkpoint blockade in hepatocellular carcinoma [RNA-seq]

PROVIDER: PRJNA690723 | ENA |

REPOSITORIES: ENA

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

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

| PRJNA690718 | ENA

A selective HDAC8 inhibitor potentiates antitumor immunity and efficacy of immune checkpoint blockade in hepatocellular carcinoma [ChIP-seq]

Project description:Insufficient T cell infiltration into non-inflamed 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 over-expressed 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 1,251 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. Importantly, mice treated with HDAC8 and PD-L1 co-blockade were protected against subsequent tumor re-challenge 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 via enhancer reprogramming.

2021-04-04 | GSE164443 | GEO

A selective HDAC8 inhibitor potentiates antitumor immunity and efficacy of immune checkpoint blockade in hepatocellular carcinoma [RNA-seq]

2021-04-04 | GSE164441 | GEO

A selective HDAC8 inhibitor potentiates antitumor immunity and efficacy of immune checkpoint blockade in hepatocellular carcinoma [ChIP-seq]

Project description:A selective HDAC8 inhibitor potentiates antitumor immunity and efficacy of immune checkpoint blockade in hepatocellular carcinoma [ChIP-seq]

| PRJNA690724 | ENA

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

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-04-04 | GSE164444 | GEO

Targeting WEE1 in tumor-associated dendritic cells potentiates antitumor immunity

Project description:DNA damage is a prevalent event within the tumor microenvironment, significantly influencing cancer initiation, progression, metastasis, and immune cell functionality. Here, we observed that oxidative stress induces DNA damage in tumor-associated dendritic cells (TADCs), leading to the activation of the serine/threonine kinase WEE1, which facilitates DNA repair. Notably, this DNA damage also acts as a stimulus for DC activation. Pharmacological inhibition of WEE1 activates TADCs via the cGAS/STING pathway, resulting in an enhanced antitumor immune response and improved tumor control. Furthermore, WEE1 inhibition augments the efficacy of DC vaccines and work synergistically with immune checkpoint blockade therapy. These findings underscore the critical role of WEE1-mediated signaling in DNA damage repair in immune cells in the tumor microenvironment, which in turn dampens the antitumor immune response. Thus, targeting WEE1 in DCs presents a promising strategy to enhance DC-mediated T cell activation and improve the effectiveness of cancer immunotherapy strategies.

2025-04-11 | GSE269330 | GEO

Melanoma Sequential Immune Checkpoint Blockade Treatment Sequencing Study

Project description:<p>Blockade of T cell coinhibitory molecules such as CTLA-4 and PD-1, can activate T cell antitumor response. Although these immune checkpoint blockades (CTLA-4 blockade and PD-1 blockade) have shown durable response, response rate is modest. Therefore, there is a need to find stable biomarkers predictive of response to immune checkpoint blockades and to understand underlying resistance mechanisms. We collected longitudinal tumor biopsies from a cohort of metastatic melanoma patients treated with sequential immune checkpoint blockades and performed whole exome sequencing of this cohort. The comprehensive genomic characterization of tumors enabled identification of higher copy number loss burden as a resistance mechanism and clonal T cell repertoire as a predictive biomarker.</p>

| phs001425 | dbGaP

Discovery of a Highly Potent and Selective HDAC3 and HDAC8 PROTAC Dual Degrader

Project description:HDAC3 and HDAC8 are members of class I deacetylases involved in several biological mechanisms and represent a highly sought-after therapeutic target for drug development. It is historically challenging to develop selective deacetylase inhibitors due to their conserved catalytic domains. HDAC3 also has deacetylase-independent activity, which cannot be blocked by conventional enzymatic inhibitors. Recent advance in proteolysis-targeting chimeras (PROTACs) provides an opportunity to eliminate the whole protein selectively, abolishing both enzymatic and scaffolding function. Here, we report a novel HDAC3/8 dual degrader YX968 that induces highly potent, rapid, and selective degradation of both HDAC3 and HDAC8 without trigging pan-HDAC inhibitory effects. Unbiased quantitative proteomics experiments further confirmed its high selectivity. This dual-specific degrader specifically ablates cellular pathways attributed to HDAC3 and HDAC8 and exhibits high potency in killing cancer cells. YX968 represents a new probe for dissecting the complex biological functions of HDAC3 and HDAC8.

2023-07-18 | GSE211758 | GEO

Targeting WEE1 in tumor-associated dendritic cells potentiates antitumor immunity [scRNA-Seq]

2025-04-11 | GSE269559 | GEO

Autophagy Inhibition via Targeting of PIKfyve Potentiates Immune Checkpoint Blockade in Prostate Cancer Therapy

Project description:Autophagy Inhibition via Targeting of PIKfyve Potentiates Immune Checkpoint Blockade in Prostate Cancer Therapy

| PRJNA730874 | ENA