Immunoproteasome Activation Expands the MHC Class I Immunopeptidome, Unmasks Neoantigens, and Enhances T-cell Anti-Myeloma Activity.

Autor:	Rana PS; Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, Ohio.; Division of Hematology and Oncology, Department of Medicine, Case Western Reserve University, Cleveland, Ohio., Ignatz-Hoover JJ; Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, Ohio.; Division of Hematology and Oncology, Department of Medicine, Case Western Reserve University, Cleveland, Ohio., Guo C; Center for Proteome Analysis, Indiana University School of Medicine, Indianapolis, Indiana.; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana., Mosley AL; Center for Proteome Analysis, Indiana University School of Medicine, Indianapolis, Indiana.; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana., Malek E; Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, Ohio.; Division of Hematology and Oncology, Department of Medicine, Case Western Reserve University, Cleveland, Ohio.; Adult Hematologic Malignancies and Stem Cell Transplant Section, Seidman Cancer Center, University Hospitals Cleveland Medical Center, Cleveland, Ohio., Federov Y; Small Molecule Drug Discovery Core, Case Western Reserve University, Cleveland, Ohio., Adams DJ; Small Molecule Drug Discovery Core, Case Western Reserve University, Cleveland, Ohio., Driscoll JJ; Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, Ohio.; Division of Hematology and Oncology, Department of Medicine, Case Western Reserve University, Cleveland, Ohio.; Adult Hematologic Malignancies and Stem Cell Transplant Section, Seidman Cancer Center, University Hospitals Cleveland Medical Center, Cleveland, Ohio.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2024 Dec 03; Vol. 23 (12), pp. 1743-1760.
DOI:	10.1158/1535-7163.MCT-23-0931
Abstrakt:	Proteasomes generate antigenic peptides that are presented on the tumor surface to cytotoxic T-lymphocytes. Immunoproteasomes are highly specialized proteasome variants that are expressed at higher levels in antigen-presenting cells and contain replacements of the three constitutive proteasome catalytic subunits to generate peptides with a hydrophobic C-terminus that fit within the groove of MHC class I (MHC-I) molecules. A hallmark of cancer is the ability to evade immunosurveillance by disrupting the antigen presentation machinery and downregulating MHC-I antigen presentation. High-throughput screening was performed to identify compound A, a novel molecule that selectively increased immunoproteasome activity and expanded the number and diversity of MHC-I-bound peptides presented on multiple myeloma cells. Compound A increased the presentation of individual MHC-I-bound peptides by >100-fold and unmasked tumor-specific neoantigens on myeloma cells. Global proteomic integral stability assays determined that compound A binds to the proteasome structural subunit PSMA1 and promotes association of the proteasome activator PA28α/β (PSME1/PSME2) with immunoproteasomes. CRISPR/Cas9 silencing of PSMA1, PSME1, or PSME2 as well as treatment with immunoproteasome-specific suicide inhibitors abolished the effects of compound A on antigen presentation. Treatment of multiple myeloma cell lines and patient bone marrow-derived CD138+ cells with compound A increased the anti-myeloma activity of allogenic and autologous T cells. Compound A was well-tolerated in vivo and co-treatment with allogeneic T cells reduced the growth of myeloma xenotransplants in NOD/SCID gamma mice. Taken together, our results demonstrate the paradigm shifting impact of immunoproteasome activators to diversify the antigenic landscape, expand the immunopeptidome, potentiate T-cell-directed therapy, and reveal actionable neoantigens for personalized T-cell immunotherapy. (©2024 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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