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NY-ESO-1 has been a major target of many immunotherapy trials because it is expressed by various cancers and is highly immunogenic. In this study, we have identified a novel HLA-B*1801-restricted CD8 +  T cell epitope, NY-ESO-1 88–96  (LEFYLAMPF) and compared its direct- and cross-presentation to that of the reported NY-ESO-1 157–165  epitope restricted to HLA-A*0201. Although both epitopes were readily cross-presented by DCs exposed to various forms of full-length NY-ESO-1 antigen, remarkably NY-ESO-1 88–96  is much more efficiently cross-presented from the soluble form, than NY-ESO-1 157–165 . On the other hand, NY-ESO-1 157–165  is efficiently presented by NY-ESO-1-expressing tumor cells and its presentation was not enhanced by IFN-γ treatment, which induced immunoproteasome as demonstrated by Western blots and functionally a decreased presentation of Melan A 26–35 ; whereas NY-ESO-1 88–96  was very inefficiently presented by the same tumor cell lines, except for one that expressed high level of immunoproteasome. It was only presented when the tumor cells were first IFN-γ treated, followed by infection with recombinant vaccinia virus encoding NY-ESO-1, which dramatically increased NY-ESO-1 expression. These data indicate that the presentation of NY-ESO-1 88–96  is immunoproteasome dependent. Furthermore, a survey was conducted on multiple samples collected from HLA-B18 +  melanoma patients. Surprisingly, all the detectable responses to NY-ESO-1 88–96  from patients, including those who received NY-ESO-1 ISCOMATRIX™ vaccine were induced spontaneously. Taken together, these results imply that some epitopes can be inefficiently presented by tumor cells although the corresponding CD8 +  T cell responses are efficiently primed  in vivo  by DCs cross-presenting these epitopes. The potential implications for cancer vaccine strategies are further discussed.

A Novel HLA-B18 Restricted CD8+ T Cell Epitope Is Efficiently Cross-Presented by Dendritic Cells from Soluble Tumor Antigen