title: Targeting CD4(+) T-helper cells improves the induction of antitumor responses in dendritic cell-based vaccination.
abstract: To evaluate the relevance of directing antigen-specific CD4(+) T helper cells as part of effective anticancer immunotherapy, we investigated the immunologic and clinical responses to vaccination with dendritic cells (DC) pulsed with either MHC class I (MHC-I)-restricted epitopes alone or both MHC class I and II (MHC-I/II)-restricted epitopes. We enrolled 33 stage III and IV HLA-A*02:01-positive patients with melanoma in this study, of whom 29 were evaluable for immunologic response. Patients received intranodal vaccinations with cytokine-matured DCs loaded with keyhole limpet hemocyanin and MHC-I alone or MHC-I/II-restricted tumor-associated antigens (TAA) of tyrosinase and gp100, depending on their HLA-DR4 status. In 4 of 15 patients vaccinated with MHC-I/II-loaded DCs and 1 of 14 patients vaccinated with MHC-I-loaded DCs, we detected TAA-specific CD8(+) T cells with maintained IFN-γ production in skin test infiltrating lymphocyte (SKIL) cultures and circulating TAA-specific CD8(+) T cells. If TAA-specific CD4(+) T-cell responses were detected in SKIL cultures, it coincided with TAA-specific CD8(+) T-cell responses. In 3 of 13 patients tested, we detected TAA-specific CD4(+)CD25(+)FoxP3(-) T cells with high proliferative capacity and IFN-γ production, indicating that these were not regulatory T cells. Vaccination with MHC-I/II-loaded DCs resulted in improved clinical outcome compared with matched control patients treated with dacarbazine (DTIC), median overall survival of 15.0 versus 8.3 months (P = 0.089), and median progression-free survival of 5.0 versus 2.8 months (P = 0.0089). In conclusion, coactivating TAA-specific CD4(+) T-helper cells with DCs pulsed with both MHC class I and II-restricted epitopes augments TAA-specific CD8(+) T-cell responses, contributing to improved clinical responses.
authors.affiliation: Department of Tumor Immunology, Radboud University Nijmegen Medical Centre (RUNMC), Nijmegen, The Netherlands.
authors.forename: Erik H J G
authors.initials: EH
authors.lastname: Aarntzen
authors.forename: I Jolanda M
authors.initials: IJ
authors.lastname: De Vries
authors.forename: W Joost
authors.initials: WJ
authors.lastname: Lesterhuis
authors.forename: Danita
authors.initials: D
authors.lastname: Schuurhuis
authors.forename: Joannes F M
authors.initials: JF
authors.lastname: Jacobs
authors.forename: Kalijn
authors.initials: K
authors.lastname: Bol
authors.forename: Gerty
authors.initials: G
authors.lastname: Schreibelt
authors.forename: Roel
authors.initials: R
authors.lastname: Mus
authors.forename: Johannes H W
authors.initials: JH
authors.lastname: De Wilt
authors.forename: John B A G
authors.initials: JB
authors.lastname: Haanen
authors.forename: Dirk
authors.initials: D
authors.lastname: Schadendorf
authors.forename: Alexandra
authors.initials: A
authors.lastname: Croockewit
authors.forename: Willeke A M
authors.initials: WA
authors.lastname: Blokx
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Van Rossum
authors.forename: William W
authors.initials: WW
authors.lastname: Kwok
authors.forename: Gosse J
authors.initials: GJ
authors.lastname: Adema
authors.forename: Cornelis J A
authors.initials: CJ
authors.lastname: Punt
authors.forename: Carl G
authors.initials: CG
authors.lastname: Figdor
mesh_terms: D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation*; D018572:Disease-Free Survival; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D053208:Kaplan-Meier Estimate; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000628:therapy*; D008875:Middle Aged; D009367:Neoplasm Staging; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D055815:Young Adult
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II