Cytosolic processing governs TAP-independent presentation of a critical melanoma antigen
Cancer immunotherapy has been flourishing in recent years with remarkable clinical success. But as more patients are treated, a shadow is emerging that has haunted other cancer therapies: tumors develop resistance. Resistance is often caused by defects in the MHC class I Ag presentation pathway crit...
| Príomhchruthaitheoirí: | , , , , |
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| Formáid: | Journal article |
| Teanga: | English |
| Foilsithe / Cruthaithe: |
American Association of Immunologists
2018
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| _version_ | 1826287135503679488 |
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| author | Vigneron, N Ferrari, V Van Den Eynde, B Cresswell, P Leonhardt, R |
| author_facet | Vigneron, N Ferrari, V Van Den Eynde, B Cresswell, P Leonhardt, R |
| author_sort | Vigneron, N |
| collection | OXFORD |
| description | Cancer immunotherapy has been flourishing in recent years with remarkable clinical success. But as more patients are treated, a shadow is emerging that has haunted other cancer therapies: tumors develop resistance. Resistance is often caused by defects in the MHC class I Ag presentation pathway critical for CD8 T cell-mediated tumor clearance. TAP and tapasin, both key players in the pathway, are frequently downregulated in human cancers, correlating with poor patient survival. Reduced dependence on these factors may promote vaccine efficiency by limiting immune evasion. In this study, we demonstrate that PMEL209-217, a promising phase 3 trial-tested antimelanoma vaccine candidate, is robustly presented by various TAP- and/or tapasin-deficient cell lines. This striking characteristic may underlie its potency as a vaccine. Surprisingly, cytosolic proteasomes generate the peptide even for TAP-independent presentation, whereas tripeptidyl peptidase 2 (TPP2) efficiently degrades the epitope. Consequently, inhibiting TPP2 substantially boosts PMEL209-217 presentation, suggesting a possible strategy to improve the therapeutic efficacy of the vaccine. |
| first_indexed | 2024-03-07T01:54:05Z |
| format | Journal article |
| id | oxford-uuid:9b211afc-be85-489e-bdc2-512519295b53 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T01:54:05Z |
| publishDate | 2018 |
| publisher | American Association of Immunologists |
| record_format | dspace |
| spelling | oxford-uuid:9b211afc-be85-489e-bdc2-512519295b532022-03-27T00:26:30ZCytosolic processing governs TAP-independent presentation of a critical melanoma antigenJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:9b211afc-be85-489e-bdc2-512519295b53EnglishSymplectic Elements at OxfordAmerican Association of Immunologists2018Vigneron, NFerrari, VVan Den Eynde, BCresswell, PLeonhardt, RCancer immunotherapy has been flourishing in recent years with remarkable clinical success. But as more patients are treated, a shadow is emerging that has haunted other cancer therapies: tumors develop resistance. Resistance is often caused by defects in the MHC class I Ag presentation pathway critical for CD8 T cell-mediated tumor clearance. TAP and tapasin, both key players in the pathway, are frequently downregulated in human cancers, correlating with poor patient survival. Reduced dependence on these factors may promote vaccine efficiency by limiting immune evasion. In this study, we demonstrate that PMEL209-217, a promising phase 3 trial-tested antimelanoma vaccine candidate, is robustly presented by various TAP- and/or tapasin-deficient cell lines. This striking characteristic may underlie its potency as a vaccine. Surprisingly, cytosolic proteasomes generate the peptide even for TAP-independent presentation, whereas tripeptidyl peptidase 2 (TPP2) efficiently degrades the epitope. Consequently, inhibiting TPP2 substantially boosts PMEL209-217 presentation, suggesting a possible strategy to improve the therapeutic efficacy of the vaccine. |
| spellingShingle | Vigneron, N Ferrari, V Van Den Eynde, B Cresswell, P Leonhardt, R Cytosolic processing governs TAP-independent presentation of a critical melanoma antigen |
| title | Cytosolic processing governs TAP-independent presentation of a critical melanoma antigen |
| title_full | Cytosolic processing governs TAP-independent presentation of a critical melanoma antigen |
| title_fullStr | Cytosolic processing governs TAP-independent presentation of a critical melanoma antigen |
| title_full_unstemmed | Cytosolic processing governs TAP-independent presentation of a critical melanoma antigen |
| title_short | Cytosolic processing governs TAP-independent presentation of a critical melanoma antigen |
| title_sort | cytosolic processing governs tap independent presentation of a critical melanoma antigen |
| work_keys_str_mv | AT vigneronn cytosolicprocessinggovernstapindependentpresentationofacriticalmelanomaantigen AT ferrariv cytosolicprocessinggovernstapindependentpresentationofacriticalmelanomaantigen AT vandeneyndeb cytosolicprocessinggovernstapindependentpresentationofacriticalmelanomaantigen AT cresswellp cytosolicprocessinggovernstapindependentpresentationofacriticalmelanomaantigen AT leonhardtr cytosolicprocessinggovernstapindependentpresentationofacriticalmelanomaantigen |