TAP-independent presentation of the melanoma vaccine candidate epitope gp100209-217 requires no gp100 sequences outside the core peptide and is sensitive to cytosolic TPP2 degradation (100.2)

Abstract

Abstract gp100209-217 is a promising anti-melanoma peptide vaccine that corresponds to an immunodominant, HLA-A*0201-restricted tumor-epitope. As an immune evasion strategy many tumors display downregulation or even total lack of expression of the TAP transporter, a crucial factor involved in MHC class I-mediated antigen presentation. Surprisingly, we find that HLA-A*0201-mediated presentation of gp100209-217 is remarkably independent of TAP and thus the peptide likely uses an unconventional pathway to access MHC class I molecules. Our data suggest that presentation does not involve proteolysis in one of the diverse protease-rich compartments that gp100 traverses on its way to melanosomes. Neither is melanosomal targeting or ER-export of gp100 required, nor is even co-translational insertion of the protein into the ER membrane necessary. However, presentation of the epitope does depend on proteasome activity. Interestingly, we find that cytosolic tripeptidyl peptidase 2 (TPP2) efficiently counteracts TAP-independent presentation of gp100209-217 suggesting that tumors might use this protease for immune evasion. Strikingly, no sequences outside the core peptide region within gp100 are required for TAP-independent access of the ligand to HLA-A*0201. We conclude that a transporter system besides TAP must exist in the cell, which can partially compensate for loss of TAP function and mediate access of critical tumor-specific antigenic peptides to HLA-A*0201.