The proteasome regulator PSME4 drives immune evasion and abrogates anti-tumor immunity in NSCLC

Abstract

Protein degradation by proteasomes is important for the immune response against tumors. Antigens generated by the proteasome promote immune cell infiltration into tumors and improve tumor response to immunotherapy. For example, immunoproteasomes – a subset of proteasomes induced by inflammatory signals – may improve the response of melanomas to immune checkpoint inhibitors (ICI) by eliciting tumor inflammation. Yet, it is unclear whether and how protein degradation by proteasomes impacts cancer progression and contributes to immune evasion and resistance. Here, we profile the proteasome-cleaved peptides in lung cancers and find that PSME4 serves as a novel inhibitory regulator of the immunoproteasome, playing an anti-inflammatory role in cancer. Biochemical assays combined with scRNA-seq, immunopeptidomics and in vivo analyses demonstrate that PSME4 promotes an immunosuppressive environment around the tumor and abrogates anti-tumor immunity by inhibiting antigen presentation and attenuating tumor inflammation. Furthermore, we find that PSME4 expression is correlated with responsiveness to ICI across several cancer types. Our findings suggest that PSME4-mediated regulation of proteasome activity is a novel mechanism of immune evasion in non-small-cell lung carcinoma and may be targeted therapeutically for restoring anti-tumor immunity.

Functional Differences between Proteasome Subtypes

“…PA200 RP is particularly abundant in the testes, and PA200-deficient mice are viable and exhibit no abnormalities except for a marked reduction in male fertility, suggesting an important role for the PA200 RP during spermatogenesis [95]. A recent study conducted by Javitt et al showed that PA200 is upregulated in cancerous tissues, and its expression in non-small-cell lung carcinoma plays an anti-inflammatory role by attenuating IP activity [96]. Finally, upon exposure to ionizing radiation, proteasomes with 19S RP on one end and PA200 on the other end accumulate on chromatin, suggesting that it may play a role in double strand break repair [94].…”

Multifactorial remodeling of the cancer immunopeptidome by interferon gamma

“…IFNg increased the expression of the 11S cap subunits which facilitate ubiquitinindependent proteasomal degradation of proteins and enhance proteasomal throughput (27)(28)(29). PSME4 is a another proteasome cap subunit, recently shown to inhibit the production of HLA-I compatible peptides (30). The decrease in PSME4 protein abundance through IFNg may further increase peptide production.…”

Identification of cryptic neoepitopes generated by chimeric transcripts in ovarian cancer

“…Tumor associated Chimeric Transcript-Protein (TcTP) burden may de ne MHC-I allele restriction by cLRPs and patient prognosis in a personalized manner While oncogenic roles have been recently assigned to CTs 31 , it is likely that several chimeric proteins may fail to achieve a stable conformation and thereby targeted for proteasomal degradation. Interestingly, recent ndings suggest cryptic neoepitopes generated through proteasomal degradation bind to MHC class I molecules and are presented to CD8 + cells in eliciting anti-tumor responses [32][33][34][35] . To evaluate a similar possible fate within the 844 tumor-speci c cLRPs in our study, we rst predicted their constitutive and immunoproteasome degradation products using the Proteasomal Cleavage Prediction Server followed by identifying good and moderate strong binding peptides to the transporter associated with antigen processing protein complex (TAP; binding scores 6-7, 7-8 and 8-9.5 respectively) on TAPPred server (Methods).…”