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The T210M substitution in the HLA-a*02:01 gp100 epitope strongly affects overall proteasomal cleavage site usage and antigen processing.

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Liepe,  J.
Research Group of Quantitative and System Biology, MPI for Biophysical Chemistry, Max Planck Society;

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Textoris-Taube, K., Keller, C., Liepe, J., Henklein, P., Sidney, J., Sette, A., et al. (2015). The T210M substitution in the HLA-a*02:01 gp100 epitope strongly affects overall proteasomal cleavage site usage and antigen processing. Journal of Biological Chemistry, 290(51), 30417-30428. doi:10.1074%2Fjbc.M115.695189.


Cite as: https://hdl.handle.net/11858/00-001M-0000-002D-FE47-2
Abstract
MHC class I-restricted epitopes, which carry a tumor-specific mutation resulting in improved MHC binding affinity, are preferred T cell receptor targets in innovative adoptive T cell therapies. However, T cell therapy requires efficient generation of the selected epitope. How such mutations may affect proteasome-mediated antigen processing has so far not been studied. Therefore, we analyzed by in vitro experiments the effect on antigen processing and recognition of a T210M exchange, which previously had been introduced into the melanoma gp100209–217tumor epitope to improve the HLA-A*02:01 binding and its immunogenicity. A quantitative analysis of the main steps of antigen processing shows that the T210M exchange affects proteasomal cleavage site usage within the mutgp100201–230 polypeptide, leading to the generation of an unique set of cleavage products. The T210M substitution qualitatively affects the proteasome-catalyzed generation of spliced and non-spliced peptides predicted to bind HLA-A or -B complexes. The T210M substitution also induces an enhanced production of the mutgp100209–217 epitope and its N-terminally extended peptides. The T210M exchange revealed no effect on ERAP1-mediated N-terminal trimming of the precursor peptides. However, mutant N-terminally extended peptides exhibited significantly increased HLA-A*02:01 binding affinity and elicited CD8+ T cell stimulation in vitro similar to the wtgp100209–217 epitope. Thus, our experiments demonstrate that amino acid exchanges within an epitope can result in the generation of an altered peptide pool with new antigenic peptides and in a wider CD8+ T cell response also towards N-terminally extended versions of the minimal epitope.