The immunodominant MART-126(27)-35 epitope, liberated from the differentiation antigen MART-1/Mel... more The immunodominant MART-126(27)-35 epitope, liberated from the differentiation antigen MART-1/Melan-A, has been frequently targeted in melanoma immunotherapy, but with limited clinical success. Previous studies suggested that this is in part due to an insufficient peptide supply and epitope presentation, since proteasomes containing the immunosubunits β5i/LMP7 or β1i/LMP2 and β5i/LMP7 interfere with MART-126-35 epitope generation in tumor cells. Here, we demonstrate that in addition the IFN-γ-inducible proteasome subunit β2i/MECL-1, proteasome activator PA28 and ER-resident aminopeptidase ERAP1 impair MART-126-35 epitope generation. β2i/MECL-1 and PA28 negatively affect C- and N-terminal cleavage and therefore epitope liberation from the proteasome, whereas ERAP1 destroys the MART-126-35 epitope by over-trimming activity. Constitutive expression of PA28 and ERAP1 in melanoma cells indicate that both interfere with MART-126-35 epitope generation even in the absence of IFN-γ. In summa...
The immunodominant MART-126(27)-35 epitope, liberated from the differentiation antigen MART-1/Mel... more The immunodominant MART-126(27)-35 epitope, liberated from the differentiation antigen MART-1/Melan-A, has been frequently targeted in melanoma immunotherapy, but with limited clinical success. Previous studies suggested that this is in part due to an insufficient peptide supply and epitope presentation, since proteasomes containing the immunosubunits β5i/LMP7 or β1i/LMP2 and β5i/LMP7 interfere with MART-126-35 epitope generation in tumor cells. Here, we demonstrate that in addition the IFN-γ-inducible proteasome subunit β2i/MECL-1, proteasome activator PA28 and ER-resident aminopeptidase ERAP1 impair MART-126-35 epitope generation. β2i/MECL-1 and PA28 negatively affect C- and N-terminal cleavage and therefore epitope liberation from the proteasome, whereas ERAP1 destroys the MART-126-35 epitope by over-trimming activity. Constitutive expression of PA28 and ERAP1 in melanoma cells indicate that both interfere with MART-126-35 epitope generation even in the absence of IFN-γ. In summa...
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Papers by Christin Keller