Targeting CD4+ T-Helper Cells Improves the Induction of Antitumor Responses in Dendritic Cell--Based Vaccination.

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+ D25+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 P 5.0 versus 2.8 months (P = 0.0089). In conclusion, coactivating TAA-specific CD4P+ 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. [ABSTRACT FROM AUTHOR]