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: Erik H J G Aarntzen, I Jolanda M De Vries, W Joost Lesterhuis, Danita Schuurhuis, Joannes F M Jacobs, Kalijn Bol, Gerty Schreibelt, Roel Mus, Johannes H W De Wilt, John B A G Haanen, Dirk Schadendorf, Alexandra Croockewit, Willeke A M Blokx, Michelle M Van Rossum, William W Kwok, Gosse J Adema, Cornelis J A Punt, Carl G Figdor
• Journal: Cancer research (Cancer Res) Vol. 73 Issue 1 Pg. 19-29 (Jan 01 2013) ISSN: 1538-7445 [Electronic] United States
• PMID: 23087058 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Neoplasm
• Cancer Vaccines
• Epitopes, T-Lymphocyte
• Histocompatibility Antigens Class I
• Histocompatibility Antigens Class II

Topics

• Adult
• Aged
• Antigens, Neoplasm (immunology)
• CD8-Positive T-Lymphocytes (immunology)
• Cancer Vaccines (immunology)
• Dendritic Cells (immunology, transplantation)
• Disease-Free Survival
• Epitopes, T-Lymphocyte (immunology)
• Female
• Flow Cytometry
• Histocompatibility Antigens Class I (immunology)
• Histocompatibility Antigens Class II (immunology)
• Humans
• Kaplan-Meier Estimate
• Lymphocyte Activation (immunology)
• Male
• Melanoma (immunology, therapy)
• Middle Aged
• Neoplasm Staging
• T-Lymphocytes, Helper-Inducer (immunology)
• Young Adult