ArticleCancer research communications2024
HDAC6 Inhibition Releases HR23B to Activate Proteasomes, Expand the Tumor Immunopeptidome and Amplify T-cell Antimyeloma Activity.
Article in Cancer research communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed.
- A next-generation HDAC6 inhibitor for amyotrophic lateral sclerosis and frontotemporal dementia.Brain : a journal of neurology · 2026Article
- Engineering TCR-directed T-cells for the treatment of multiple myeloma.Frontiers in immunology · 2026Review
- Revolutions at the frontline of multiple myeloma treatment: lessons and challenges to finding a cure.Frontiers in oncology · 2025Review
- The regulatory mechanisms and treatment of HDAC6 in immune dysregulation diseases.Frontiers in immunology · 2025Review
- A review of recent clinical trials to evaluate disease-modifying therapies in the treatment of cardiac amyloidosis.Frontiers in medicine · 2024Review
Corrections and comments
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Authors and funding
8 authors.
Funding
Abstract
Proteasomes degrade intracellular proteins to generate antigenic peptides that are recognized by the adaptive immune system and promote anticancer immunity. However, tumors subvert the antigen presentation machinery to escape immunosurveillance. We hypothesized that proteasome activation could concomitantly increase antigen abundance and diversity in multiple myeloma cells. High-throughput screens revealed that histone deacetylase 6 (HDAC6) inhibitors activated proteasomes to unmask neoantigens and amplify the tumor-specific antigenic landscape. Treatment of patient CD138+ cells with HDAC6 inhibitors significantly promoted the antimyeloma activity of autologous CD8+ T cells. Pharmacologic blockade and genetic ablation of the HDAC6 ubiquitin-binding domain released HR23B, which shuttles ubiquitinylated cargo to proteasomes, while silencing HDAC6 or HR23B in multiple myeloma cells abolished the effect of HDAC6 inhibitors on proteasomes, antigen presentation, and T-cell cytotoxicity. Taken together, our results demonstrate the paradigm-shifting translational impact of proteasome activators to expand the myeloma immunopeptidome and have revealed novel, actionable antigenic targets for T cell-directed immunotherapy. SIGNIFICANCE: The elimination of therapy-resistant tumor cells remains a major challenge in the treatment of multiple myeloma. Our study identifies and functionally validates agents that amplify MHC class I-presented antigens and pave the way for the development of proteasome activators as immune adjuvants to enhance immunotherapeutic responses in patients with multiple myeloma.
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