Neutrophil-dependent tumor rejection and priming of tumoricidal CD8+ T cell response induced by dendritic cells overexpressing CD95L.
Overexpression of CD95 (Fas/Apo-1) ligand (CD95L) has been shown to induce T cell tolerance but also, neutrophilic inflammation and rejection of allogeneic tissue. We explored the capacity of dendritic cells (DCs) genetically engineered to overexpress CD95L to induce an antitumor response. We first found that DCs overexpressing CD95L, in addition to MHC class I-restricted OVA peptides (CD95L-OVA-DCs), induced increased antigen-specific CD8(+) T cell responses as compared with DCs overexpressing OVA peptides alone. The enhanced T cell responses were associated with improved regression of a tumor expressing OVA, allowing survival of all animals. When DCs overexpressing CD95L (CD95L-DCs) were injected with the tumor expressing OVA, in vivo tumor proliferation was strikingly inhibited. A strong cellular apoptosis and a massive neutrophilic infiltrate developed in this setting. Neutrophil depletion prevented tumor regression as well as enhanced IFN-gamma production induced by CD95L-OVA-DCs. Furthermore, the CD8(+) T cell response induced by the coadministration of tumor cells and CD95L-DCs led to rejection of a tumor implanted at a distance from the DC injection site. In summary, DCs expressing CD95L promote tumor rejection involving neutrophil-mediated innate immunity and CD8(+) T cell-dependent adaptative immune responses.
Institute for Medical Immunology, Université Libre de Bruxelles, Rue Adrienne Bolland 8, 6041 Gosselies, Belgium.
Sofia
S
Buonocore
Najate Ouled
NO
Haddou
Fabrice
F
Moore
Sandrine
S
Florquin
Frédéric
F
Paulart
Carlo
C
Heirman
Kris
K
Thielemans
Michel
M
Goldman
Véronique
V
Flamand
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001853:Bone Marrow; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002450:Cell Communication; D003713:Dendritic Cells / Q000166:cytology / Q000502:physiology*; D053222:Fas Ligand Protein / Q000276:immunology / Q000378:metabolism*; D005805:Genes, MHC Class I; D007114:Immunization; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000276:immunology*; D010047:Ovalbumin / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D016038:Skin Transplantation; D015996:Survival Rate; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D013945:Thymoma / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D014162:Transfection; D014611:Vaccination; D019014:fas Receptor / Q000378:metabolism
D053222:Fas Ligand Protein; D010446:Peptide Fragments; D019014:fas Receptor; D007371:Interferon-gamma; D010047:Ovalbumin