Adjuvanticity of plasmid DNA encoding cytokines fused to immunoglobulin Fc domains.
OBJECTIVE
Plasmid DNAs encoding cytokines enhance immune responses to vaccination in models of infectious diseases and cancer. We compared DNA adjuvants for their ability to enhance immunity against a poorly immunogenic self-antigen expressed by cancer.


METHODS
DNAs encoding cytokines that affect T cells [interleukin (IL)-2, IL-12, IL-15, IL-18, IL-21, and the chemokine CCL21] and antigen-presenting cells [granulocyte macrophage colony-stimulating factor (GM-CSF)] were compared in mouse models as adjuvants to enhance CD8+ T-cell responses and tumor immunity. A DNA vaccine against a self-antigen, gp100, expressed by melanoma was used in combination with DNA encoding cytokines and cytokines fused to the Fc domain of mouse IgG1 (Ig).


RESULTS
We found that (a) cytokine DNAs generally increased CD8+ T-cell responses against gp100; (b) ligation to Fc domains further enhanced T-cell responses; (c) adjuvant effects were sensitive to timing of DNA injection; (d) the most efficacious individual adjuvants for improving tumor-free survival were IL-12/Ig, IL-15/Ig, IL-21/Ig, GM-CSF/Ig, and CCL21; and (e) combinations of IL-2/Ig+IL-12/Ig, IL-2/Ig+IL-15/Ig, IL-12/Ig+IL-15/Ig, and IL-12/Ig+IL-21/Ig were most active; and (f) increased adjuvanticity of cytokine/Ig fusion DNAs was not related to higher tissue levels or greater stability.


CONCLUSIONS
These observations support the potential of cytokine DNA adjuvants for immunization against self-antigens expressed by cancer, the importance of timing, and the enhancement of immune responses by Fc domains through mechanisms unrelated to increased half-life.
Ferrone
Cristina R
CR
The Swim Across America Laboratory, Memorial Sloan-Kettering Cancer Center, Weill Medical and Graduate Schools of Cornell University, New York, NY 10021, USA.
Perales
Miguel-Angel
MA
Goldberg
Stacie M
SM
Somberg
C Joy
CJ
Hirschhorn-Cymerman
Daniel
D
Gregor
Polly D
PD
Turk
Mary Jo
MJ
Ramirez-Montagut
Teresa
T
Gold
Jason S
JS
Houghton
Alan N
AN
Wolchok
Jedd D
JD
D000210:Acute-Phase Reaction / Q000276:immunology; D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001324:Autoantigens / Q000276:immunology; D016827:CD8 Antigens / Q000378:metabolism; D016207:Cytokines / Q000235:genetics* / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology; D017496:Hypopigmentation / Q000276:immunology; D007141:Immunoglobulin Fc Fragments / Q000235:genetics; D016233:Immunotherapy, Active / Q000009:adverse effects / Q000379:methods* / Q000706:statistics & numerical data; D018664:Interleukin-12 / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000276:immunology*; D010957:Plasmids / Q000737:chemistry / Q000276:immunology; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors; D019444:Vaccines, DNA / Q000009:adverse effects / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D000276:Adjuvants, Immunologic; D001324:Autoantigens; D016827:CD8 Antigens; D016207:Cytokines; D007141:Immunoglobulin Fc Fragments; D019444:Vaccines, DNA; D018664:Interleukin-12