Background: NY-ESO-1 is a cancer testis antigen, expressed in germ cells and upregulated in many human tumours. It is highly immunogenic and an attractive target for therapeutic cancer vaccination.
Degradation of cellular proteins by the proteasome is critical to the generation of MHC-associated peptides. The constitutive ‘standard’ proteasome (cP) and the IFN-gamma-induced immunoproteasome (iP) differ in the use of three catalytic beta subunits, which alters production of MHC class I epitopes. Dendritic cells (DC) constitutively express iPs, whereas melanoma iP expression is infrequent. The potential for a differential repertoire of epitopes produced between DC and tumour cells thus arises.
Method: We studied presentation of three NY-ESO-1 HLA-Cw3 restricted epitopes by melanoma cell lines. Using antigen specific T cell clones we assessed surface presentation of each epitope. We induced expression of iPs in melanoma cells with IFN gamma, and demonstrated differences in presentation of each epitope following processing through the iP. We further investigated processing of these epitopes by selective inhibition of the iP catalytic subunit LMP7 using a small molecule inhibitor, or by siRNA knockdown.
Conclusions: The differences observed in presentation of all three NY-ESO-1 epitopes following iP processing, highlight a discrepancy in presentation of described immunodominant epitopes between DC and melanoma cells. Results may explain why previously observed vaccine-induced immune responses to NY-ESO-1 failed to result in objective clinical responses in patients. Awareness of how individual cancer epitopes are processed by melanoma cells is therefore critical to future development of therapeutic cancer vaccines.