title: Immunoproteasomes edit tumors, which then escapes immune recognition.
abstract: In 1985, John Monaco--the discoverer of LMP-2 and -7, the inducible components of the immunoproteasome--asked his advanced immunology class as to why the MHC region contained not only structural genes, but several others as well, whose functions were then unknown. As we drew a blank, he quipped: perchance because many of the MHC genes are induced by IFN-γ! The ensuing three decades have witnessed the unveiling of the profound fundamental and clinical implications of that classroom tête-à-tête. Amongst its multitudinous effects, IFN-γ induces genes enhancing antigen processing and presentation to T cells; such as those encoding cellular proteases and activators of proteases. In this issue, Keller et al. [Eur. J. Immunol. 2015. 45: 3257-3268] demonstrate that the limited success of MART-1/Melan-A-targeted immunotherapy in melanoma patients could be due to inefficient MART-1(26-35) presentation, owing to the proteolytic activities of IFN-γ-inducible β2i/MECL-1, proteasome activator 28 (PA28), and endoplasmic reticulum-associated aminopeptidase-associated with antigen processing (ERAP). Specifically, whilst β2i and PA28 impede MART-1(26-35) liberation from its precursor protein, ERAP-1 degrades this epitope. Hence, critical to effective cancer immunotherapy is deep knowledge of T-cell-targeted tumor antigens and how cellular proteases generate protective epitope(s) from them, or destroy them.
authors.affiliation: Veterans Administration Tennessee Valley Healthcare System and the Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Joyce
mesh_terms: D000818:Animals; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D058965:MART-1 Antigen / Q000276:immunology; D008545:Melanoma / Q000276:immunology / Q000628:therapy; D046988:Proteasome Endopeptidase Complex / Q000276:immunology*; D019139:Tumor Escape
chemical_list: D058965:MART-1 Antigen; D007371:Interferon-gamma; D046988:Proteasome Endopeptidase Complex
keywords: Antigen processing; Cellular cytotoxicity; ER-aminopeptidase; Immunoroteasome subunit; Melanoma; Melanoma antigen recognized by T cells/melanoma antigen A; PA28; Standard proteasome subunit