Tumors escape immunosurveillance by overexpressing the proteasome activator PSME3

Abstract

The success of CD8 + T cell-based cancer immunotherapy emphasizes the importance of understanding the mechanisms of generation of MHC-I peptide ligands and the possible pathways of tumor cell escape from immunosurveillance. Recently, we showed that peptides generated in the nucleus during a pioneer round of mRNA translation (pioneer translation products, or PTPs) are an important source of tumor specific peptides which correlates with the aberrant splicing and transcription events associated with oncogenesis. Here we show that up-regulation of PSME3 proteasome activator in cancer cells results in increased destruction of PTP-derived peptides in the nucleus thus enabling cancer cell to subvert immunosurveillance. These findings unveil a previously unexpected role for PSME3 in antigen processing and identify PSME3 as a druggable target to improve the efficacy of cancer immunotherapy.

PA28γ: New Insights on an Ancient Proteasome Activator

“…Accordingly, in vitro degradation with purified proteasomes of a long precursor (52mer) containing an embedded epitope sequence showed complete hydrolysis into small fragments of the antigenic peptides when 20S was associated with PA28γ, while in its absence generation of the epitope was clearly detectable. Consistent with these observations, knockout of PA28γ was found to negatively impact tumor growth in a mouse model, an effect that was partly dependent on the ability of PA28γ to impair the immunosurveillance process [131]. The ability of PA28γ to reduce MHC class I presentation and to counteract autoimmunity was also recently reported by Yao L. et al [135].…”

“…However, more recent studies pointed out that PA28γ has specific functions that are related to the proper functioning of the immune system. Overexpression of PA28γ was shown to markedly decrease MHC class I presentation of epitopes derived from PTPs (Pioneer Translation Products) in cancer cell lines, while its reduction leads to the opposite result [ 131 ]. PTPs are polypeptides produced in the nucleus by a non-canonical translation event prior to mRNA splicing and whose generation is specifically enhanced in cancers due to aberrant mRNA transcription and maturation processes that are typically associated with oncogenesis.…”

“…Interestingly, in this case the immunosuppressive effect observed in mouse bone marrow-derived and splenic dendritic cells (DCs), MEFs, and HeLa cells seems to be achieved through down-regulating the expression of immunoproteasome consequent to enhanced proteasomal degradation of phosphorylated STAT-3. However, in other mouse and human cell lines no major effect of PA28γ on the expression levels of immunoproteasome in basal conditions or under interferon-γ stimulation could be detected [ 131 ]. Further studies are thus necessary to establish the role of PA28γ in modulating the levels of immunoproteasome in different cell types and in physiological and pathological contexts.…”

“…Accordingly, by combining HP-size exclusion chromatography with LC-MS/MS tandem mass spectrometry sequencing and signal intensity-based relative quantification, it was demonstrated that PA28αβ profoundly modifies the entire spectrum of peptides generated by the 20S proteasome during degradation of full-length proteins, with a clear reduction of mean and median size of products, and a concomitant preferential release of specific, more hydrophilic, and longer peptides [ 37 ]. Conversely, no overall difference in terms of mean and median size was detected when a similar analysis was performed on the products released by the 20S proteasome in the presence or absence of PA28γ [ 61 ], although in related studies did demonstrate an effect on the rates of generation of specific individual peptides [ 131 ]. Overall, these data seem to confirm that PA28γ has a prevalent action aimed at increasing the degradation rates of unstructured proteins, while PA28αβ exerts a function mainly directed at modifying the spectrum of peptides released by the proteasome.…”

Identification and Validation of Immune-Related Gene Signature for Predicting Lymph Node Metastasis and Prognosis in Lung Adenocarcinoma

“…Proteasome activator subunit 3 (PSME3), a subunit of the 11SREG-γ proteasome regulator, is associated with the proteasome and is known to regulate the degradation of the cell cycle protein-dependent kinase inhibitors p21 and p16, the oncogene SRC-3 and the tumor suppressor p53 ( Li et al, 2007 ; Zhang and Zhang, 2008 ). In addition, recent studies have revealed that tumors evade immune surveillance by overexpressing PSME3 ( Boulpicante et al, 2020 ). It was proposed in previous studies that S100A6 acts as a calcium sensor and regulator to promote cellular calcium signaling and, in lung cancer, promotes cancer cell proliferation, invasion, and migration through P53 acetylation ( Emberley et al, 2004 ).…”