Dendritic Cells Loaded With mRNA Encoding Full-length Tumor Antigens Prime CD4 super(+) and CD8 super(+) T Cells in Melanoma Patients

• Published in: Molecular therapy Vol. 20; no. 5; pp. 1063 - 1074
• Main Authors: Van Nuffel, An MT, Benteyn, Daphne, Wilgenhof, Sofie, Pierret, Lauranne, Corthals, Jurgen, Heirman, Carlo, van der Bruggen, Pierre, Coulie, Pierre G, Neyns, Bart, Thielemans, Kris, Bonehill, Aude
• Format: Journal Article
• Language: English
• Published: 01-05-2012
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1038/mt.2012.11

It is generally thought that dendritic cells (DCs) loaded with full-length tumor antigen could improve immunotherapy by stimulating broad T-cell responses and by allowing treatment irrespective of the patient's human leukocyte antigen (HLA) type. To investigate this, we determined the specificity of T cells from melanoma patients treated with DCs loaded with mRNA encoding a full-length tumor antigen fused to a signal peptide and an HLA class II sorting signal, allowing presentation in HLA class I and II. In delayed-type hypersensitive (DTH)-biopsies and blood, we found functional CD8 super(+) and CD4 super(+) T cells recognizing novel treatment-antigen-derived epitopes, presented by several HLA types. Additionally, we identified a CD8 super(+) response specific for the signal peptide incorporated to elicit presentation by HLA class II and a CD4 super(+) response specific for the fusion region of the signal peptide and one of the antigens. This demonstrates that the fusion proteins contain newly created immunogenic sequences and provides evidence that ex vivo-generated mRNA-modified DCs can induce effector CD8 super(+) and CD4 super(+) T cells from the naive T-cell repertoire of melanoma patients. Thus, this work provides definitive proof that DCs presenting the full antigenic spectrum of tumor antigens can induce T cells specific for novel epitopes and can be administered to patients irrespective of their HLA type.