The HDAC inhibitor zabadinostat is a systemic regulator of adaptive immunity

Li, Geng; Barczak, Wojciech; Lee, Lian Ni; Shrestha, Amit; Provine, Nicholas M.; Albayrak, Gulsah; Zhu, Hong; Hutchings, Claire; Klenerman, Paul; Thangue, N B La

doi:10.1038/s42003-023-04485-y

Cited by 9 publications

(3 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, recent reports have indicated that HDACi can stimulate the expression of MHC-II genes. 27 Consistent with these findings, we observed that QAPHA treatment induced the expression of MHC-II molecules on CD45cells from TC-1 tumors treated with QAPHA (figure 3E,F) and in TC-1 Luc+cells in vitro in a dose-dependent manner (online supplemental figure 3D). In vivo, the smallest TC-1 tumors exhibited higher MHC-II expression at their cell surface (figure 3G) highlighting the involvement of MHC-II expression QAPHA-induced antitumor response.…”

Section: Qapha Antitumor Effect Is Mediated By Cd4 Ctls Recruitmentsupporting

confidence: 85%

Dual molecule targeting HDAC6 leads to intratumoral CD4+ cytotoxic lymphocytes recruitment through MHC-II upregulation on lung cancer cells

Ducellier,

Demeules,

Letribot

et al. 2024

J Immunother Cancer

View full text Add to dashboard Cite

BackgroundDespite the current therapeutic treatments including surgery, chemotherapy, radiotherapy and more recently immunotherapy, the mortality rate of lung cancer stays high. Regarding lung cancer, epigenetic modifications altering cell cycle, angiogenesis and programmed cancer cell death are therapeutic targets to combine with immunotherapy to improve treatment success. In a recent study, we uncovered that a molecule called QAPHA ((E)−3-(5-((2-cyanoquinolin-4-yl)(methyl)amino)−2-methoxyphenyl)-N-hydroxyacrylamide) has a dual function as both a tubulin polymerization and HDAC inhibitors. Here, we investigate the impact of this novel dual inhibitor on the immune response to lung cancer.MethodsTo elucidate the mechanism of action of QAPHA, we conducted a chemical proteomics analysis. Using an in vivo mouse model of lung cancer (TC-1 tumor cells), we assessed the effects of QAPHA on tumor regression. Tumor infiltrating immune cells were characterized by flow cytometry.ResultsIn this study, we first showed that QAPHA effectively inhibited histone deacetylase 6, leading to upregulation of HSP90, cytochrome C and caspases, as revealed by proteomic analysis. We confirmed that QAPHA induces immunogenic cell death (ICD) by expressing calreticulin at cell surface in vitro and demonstrated its efficacy as a vaccine in vivo. Remarkably, even at a low concentration (0.5 mg/kg), QAPHA achieved complete tumor regression in approximately 60% of mice treated intratumorally, establishing a long-lasting anticancer immune response. Additionally, QAPHA treatment promoted the infiltration of M1-polarized macrophages in treated mice, indicating the induction of a pro-inflammatory environment within the tumor. Very interestingly, our findings also revealed that QAPHA upregulated major histocompatibility complex class II (MHC-II) expression on TC-1 tumor cells both in vitro and in vivo, facilitating the recruitment of cytotoxic CD4+T cells (CD4+CTL) expressing CD4+, NKG2D+, CRTAM+, and Perforin+. Finally, we showed that tumor regression strongly correlates to MHC-II expression level on tumor cell and CD4+CTL infiltrate.ConclusionCollectively, our findings shed light on the discovery of a new multitarget inhibitor able to induce ICD and MHC-II upregulation in TC-1 tumor cell. These two processes participate in enhancing a specific CD4+cytotoxic T cell-mediated antitumor response in vivo in our model of lung cancer. This breakthrough suggests the potential of QAPHA as a promising agent for cancer treatment.

show abstract

Section: Qapha Antitumor Effect Is Mediated By Cd4 Ctls Recruitmentsupporting

confidence: 85%

Dual molecule targeting HDAC6 leads to intratumoral CD4+ cytotoxic lymphocytes recruitment through MHC-II upregulation on lung cancer cells

Ducellier,

Demeules,

Letribot

et al. 2024

J Immunother Cancer

View full text Add to dashboard Cite

show abstract

“…223 Frequent alterations of HDACs in human cancers make them attractive cancer targets for the discovery and development of small molecule inhibitors. 224,225 Indeed, HDAC inhibitors were found to induce cell cycle arrest, cell death, and differentiation, to blocked angiogenesis as well as to modulate immune response, and few inhibitors have been approved for the treatment of some T-cell lymphoma and multiple myeloma. 226 Currently, the major challenge of achieving complex selectivity with HDAC inhibitors is considered to be a major source of off-target toxicity and adverse reactions associated with HDAC inhibitors.…”

Section: Hdacmentioning

confidence: 99%

“…Histone deacetylases (HDACs) removes acetyl‐group mainly from histones, thus acting as “epigenetic erases” to play a crucial role in modification of chromosome structure and regulation of gene expression 223 . Frequent alterations of HDACs in human cancers make them attractive cancer targets for the discovery and development of small molecule inhibitors 224,225 . Indeed, HDAC inhibitors were found to induce cell cycle arrest, cell death, and differentiation, to blocked angiogenesis as well as to modulate immune response, and few inhibitors have been approved for the treatment of some T‐cell lymphoma and multiple myeloma 226 …”

Section: Vhl Ligands and Their Utilizations In Protacs For Cancer Dru...mentioning

confidence: 99%

PROTACs: A novel strategy for cancer drug discovery and development

Han

Sun

2023

MedComm

View full text Add to dashboard Cite

Proteolysis targeting chimera (PROTAC) technology has become a powerful strategy in drug discovery, especially for undruggable targets/proteins. A typical PROTAC degrader consists of three components: a small molecule that binds to a target protein, an E3 ligase ligand (consisting of an E3 ligase and its small molecule recruiter), and a chemical linker that hooks first two components together. In the past 20 years, we have witnessed advancement of multiple PRO-TAC degraders into the clinical trials for anticancer therapies. However, one of the major challenges of PROTAC technology is that only very limited number of E3 ligase recruiters are currently available as E3 ligand for targeted protein degradation (TPD), although human genome encodes more than 600 E3 ligases. Thus, there is an urgent need to identify additional effective E3 ligase recruiters for TPD applications. In this review, we summarized the existing RING-type E3 ubiquitin ligase and their small molecule recruiters that act as effective E3 ligands of PRO-TAC degraders and their application in anticancer drug discovery. We believe that this review could serve as a reference in future development of efficient E3 ligands of PROTAC technology for cancer drug discovery and development.

show abstract

Sustained cancer‐relevant alternative RNA splicing events driven by PRMT5 in high‐risk neuroblastoma

Bate‐Eya,

Albayrak,

Carr

et al. 2024

Molecular Oncology

View full text Add to dashboard Cite

Protein arginine methyltransferase 5 (PRMT5) is over‐expressed in a wide variety of cancers and is implicated as having a key oncogenic role, achieved in part through its control of the master transcription regulator E2F1. We investigated the relevance of PRMT5 and E2F1 in neuroblastoma (NB) and found that elevated expression of PRMT5 and E2F1 occurs in poor prognosis high‐risk disease and correlates with an amplified Myelocytomatosis viral‐related oncogene, neuroblastoma‐derived (MYCN) gene. Our results show that MYCN drives the expression of splicing factor genes that, together with PRMT5 and E2F1, lead to a deregulated alternative RNA splicing programme that impedes apoptosis. Pharmacological inhibition of PRMT5 or inactivation of E2F1 restores normal splicing and renders NB cells sensitive to apoptosis. Our findings suggest that a sustained cancer‐relevant alternative RNA splicing programme desensitises NB cells to apoptosis, and identify PRMT5 as a potential therapeutic target for high‐risk disease.

show abstract

The HDAC inhibitor zabadinostat is a systemic regulator of adaptive immunity

Cited by 9 publications

References 33 publications

Dual molecule targeting HDAC6 leads to intratumoral CD4+ cytotoxic lymphocytes recruitment through MHC-II upregulation on lung cancer cells

Dual molecule targeting HDAC6 leads to intratumoral CD4+ cytotoxic lymphocytes recruitment through MHC-II upregulation on lung cancer cells

PROTACs: A novel strategy for cancer drug discovery and development

Sustained cancer‐relevant alternative RNA splicing events driven by PRMT5 in high‐risk neuroblastoma

Contact Info

Product

Resources

About