figure
posted on 2024-06-18, 14:20 authored by Priyanka S. Rana, James J. Ignatz-Hoover, Byung-Gyu Kim, Ehsan Malek, Yuriy Federov, Drew Adams, Timothy Chan, James J. Driscoll <p>Fig. S19. Graphical representation to depict the effect of HDAC6 inhibitors on proteasome activity. HDAC6 inhibitors release HR23B which is bound to the HDAC6 BUZ domain. Free HR23B binds and shuttles ubiquitinated cargo proteins to the proteasome. Rad23 binds the proteasome through a UbL (ubiquitin-like) domain and contains UBA (ubiquitin-associated) motifs that bind multi-ubiquitin chains. These domains allow Rad23 to function as a substrate shuttle-factor. Shown is the association of HR23B with the 26S proteasome through interaction with the non-ATPase regulatory subunit 14, also known as Rpn11. The ability of HDAC6 to downregulate HR23B occurs independently of its deacetylase activity.</p>
Funding
Vinney Foundation
HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)
History
ARTICLE 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.
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.
