Processing and cross-presentation of individual HLA-A, -B, or -C epitopes from NY-ESO-1 or an HLA-A epitope for Melan-A differ according to the mode of antigen delivery.

Abstract

The ability of dendritic cells (DCs) to cross-present protein tumor antigens to cytotoxic T lymphocytes (CTLs) underpins the success of therapeutic cancer vaccines. We studied cross-presentation of the cancer/testis antigen, NY-ESO-1, and the melanoma differentiation antigen, Melan-A by human DC subsets. Monocyte-derived DCs (MoDCs) efficiently cross-presented human leukocyte associated (HLA)-A2-restricted epitopes from either a formulated NY-ESO-1/ISCOMATRIX vaccine or when either antigen was mixed with ISCOMATRIX adjuvant. HLA-A2 epitope generation required endosomal acidification and was proteasome-independent for NY-ESO-1 and proteasome-dependent for Melan-A. Both MoDCs and CD1c(+) blood DCs cross-presented NY-ESO-1-specific HLA-A2(157-165)-, HLA-B7(60-72)-, and HLA-Cw3(92-100)-restricted epitopes when formulated as an NY-ESO-1/ISCOMATRIX vaccine, but this was limited when NY-ESO-1 and ISCOMATRIX adjuvant were added separately to the DC cultures. Finally, cross-presentation of NY-ESO-1(157-165)/HLA-A2, NY-ESO-1(60-72)/HLA-B7, and NY-ESO-1(92-100)/HLA-Cw3 epitopes was proteasome-dependent when formulated as immune complexes (ICs) but only proteasome-dependent for NY-ESO-1(60-72)/HLA-B7-restricted cross-presentation facilitated by ISCOMATRIX adjuvant. We demonstrate, for the first time, proteasome-dependent and independent cross-presentation of HLA-A-, B-, and C-restricted epitopes within the same full-length tumor antigen by human DCs. Our findings identify important differences in the capacities of human DC subsets to cross-present clinically relevant, full-length tumor antigens and how vaccine formulation impacts CTL responses in vivo.

• Authors: Neil C Robson, Tristan McAlpine, Ashley J Knights, Max Schnurr, Amanda Shin, Weisan Chen, Eugene Maraskovsky, Jonathan Cebon
• Journal: Blood (Blood) Vol. 116 Issue 2 Pg. 218-25 (Jul 15 2010) ISSN: 1528-0020 [Electronic] United States
• PMID: 20430956 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Neoplasm
• Cancer Vaccines
• Drug Combinations
• Epitopes, T-Lymphocyte
• HLA-A Antigens
• HLA-B Antigens
• HLA-C Antigens
• Histocompatibility Antigens Class I
• ISCOMATRIX
• MART-1 Antigen
• MLANA protein, human
• Neoplasm Proteins
• Peptide Fragments
• Phospholipids
• Saponins
• peptide NY-ESO-1 157-165
• Cholesterol
• Proteasome Endopeptidase Complex

Topics

• Antigen Presentation (immunology)
• Antigens, Neoplasm (immunology)
• Cancer Vaccines (immunology)
• Cholesterol (immunology)
• Cross-Priming (immunology)
• Dendritic Cells (immunology)
• Drug Combinations
• Epitopes, T-Lymphocyte (immunology)
• HLA-A Antigens (immunology)
• HLA-B Antigens (immunology)
• HLA-C Antigens (immunology)
• Histocompatibility Antigens Class I (immunology)
• Humans
• Lymphocyte Activation (immunology)
• MART-1 Antigen
• Neoplasm Proteins (immunology)
• Peptide Fragments (immunology)
• Phospholipids (immunology)
• Proteasome Endopeptidase Complex (immunology)
• Saponins (immunology)