CD40 cross-linking bypasses the absolute requirement for CD4 T cells during immunization with melanoma antigen gene-modified dendritic cells

Genetic immunization of mice with dendritic cells (DCs) engineered to express a melanoma antigen generates antigen-specific, MHC-restricted, CD4-dependent protective immune responses. We wanted to determine the role of CD4 cells and CD40 ligation of MART-1 gene-modified DC in an animal model of immu...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2001-12, Vol.61 (24), p.8787-8793
Main Authors: RIBAS, Antoni, BUTTERFIELD, Lisa H, ECONOMOU, James S, AMARNANI, Saral N, DISSETTE, Vivian B, KIM, Donald, MENG, Wilson S, MIRANDA, Gustavo A, WANG, He-Jing, MCBRIDE, William H, GLASPY, John A
Format: Article
Language:English
Subjects:
Adenoviridae - genetics
Animals
Antigens, Neoplasm
Antineoplastic agents
Biological and medical sciences
CD4-Positive T-Lymphocytes - immunology
CD40 Antigens - genetics
CD40 Antigens - immunology
CD40 Antigens - metabolism
CD40 Ligand - genetics
CD40 Ligand - immunology
CD8-Positive T-Lymphocytes - immunology
Cytotoxicity, Immunologic - immunology
Dendritic Cells - immunology
Dendritic Cells - metabolism
Dendritic Cells - physiology
Epitopes, T-Lymphocyte - immunology
Genetic Vectors - genetics
Immunotherapy
Immunotherapy, Adoptive - methods
Interleukins - biosynthesis
Interleukins - genetics
Interleukins - immunology
Lymphoma - immunology
Lymphoma - therapy
MART-1 Antigen
Medical sciences
Melanoma, Experimental - immunology
Melanoma, Experimental - prevention & control
Melanoma, Experimental - therapy
Mice
Mice, Inbred C57BL
Mice, Knockout
Neoplasm Proteins - genetics
Neoplasm Proteins - immunology
Pharmacology. Drug treatments
Transduction, Genetic
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Summary:Genetic immunization of mice with dendritic cells (DCs) engineered to express a melanoma antigen generates antigen-specific, MHC-restricted, CD4-dependent protective immune responses. We wanted to determine the role of CD4 cells and CD40 ligation of MART-1 gene-modified DC in an animal model of immunotherapy for murine melanoma. CD4 knock-out (CD4KO) or antibody-depleted mice were immunized with DC adenovirally transduced with the MART-1 gene (AdVMART1/DC) with or without CD40 cross-linking. Tumor protection was absent in CD4-depleted mice, but protection was reestablished when the CD40 receptor was engaged using three different constructs. Transduction of DCs with vectors expressing the Th1 cytokines interleukin (IL)-2, IL-7, or IL-12 could not reproduce the CD40-mediated maturation signal in this model. CD8 T-cell depletion in CD4KO mice immunized with CD40-ligated DCs abrogated the protective response. Pooled analysis of CD40 cross-linking of AdVMART1/DC administered to wild-type C57BL/6 mice revealed an overall enhancement of antitumor immunity. However, this effect was inconsistent between replicate studies. In conclusion, maturation of AdVMART1-transduced DCs through the CD40 ligation pathway can promote a protective CD8 T-cell-mediated immunity that is independent of CD4 T-cell help.
ISSN:0008-5472
1538-7445