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 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.
Ribas
A
A
Division of Surgical Oncology, University of California at Los Angeles, Los Angeles, California 90095, USA.
Butterfield
L H
LH
Amarnani
S N
SN
Dissette
V B
VB
Kim
D
D
Meng
W S
WS
Miranda
G A
GA
Wang
H J
HJ
McBride
W H
WH
Glaspy
J A
JA
Economou
J S
JS
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000951:Antigens, Neoplasm; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D023201:CD40 Ligand / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005822:Genetic Vectors / Q000235:genetics; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D008223:Lymphoma / Q000276:immunology / Q000628:therapy; D058965:MART-1 Antigen; D008546:Melanoma, Experimental / Q000276:immunology* / Q000517:prevention & control / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology; D014161:Transduction, Genetic
D000951:Antigens, Neoplasm; D019013:CD40 Antigens; D018984:Epitopes, T-Lymphocyte; D007378:Interleukins; D058965:MART-1 Antigen; C548668:Mlana protein, mouse; D009363:Neoplasm Proteins; D023201:CD40 Ligand