Boulpicante et al. showed that proteasome activator PSME3 degrades MHC-I antigen from pioneer translation products in the nucleus and suppresses immunosurveillance. Increased PSME3 expression levels correlated with decreased MHC-I antigen presentation in cancer cells. PSME3 knockdown or knockout increased the antigen presentation and T cell activation in vitro. PSME3-mediated MHC-I antigen degradation was dependent on PSME3-20S proteasome interaction in the nucleus. PSME3 knockdown reduced tumor growth in the sarcoma model, which was partially dependent on adaptive immunity.
Contributed by Shishir Pant
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.