DNA vaccination with all-trans retinoic acid treatment induces long-term survival and elicits specific immune responses requiring CD4+ and CD8+ T-cell activation in an acute promyelocytic leukemia mouse model.
DNA vaccination and all-trans retinoic acid (ATRA) result in a survival advantage in a mouse model of acute promyelocytic leukemia (APL). Depletion of CD4(+) or CD8(+) cells abolished this effect. CD4(+) depletions of long-term survivors resulted in relapse and death within 3 months, thus demonstrating the need of both CD4(+) and CD8(+) subsets for the generation of DNA-driven antileukemic immune responses and underscoring a crucial role of CD4(+) cells in the maintenance of durable remissions. Degranulation and cytotoxic carboxyfluorescein diacetate succinimidyl ester-based assays showed major histocompatibility complex-restricted APL-specific T cell-mediated immune responses. Sorted APL-specific CD8(+)CD107a(+) T cells showed an increase of antileukemic activity. Effectors from ATRA + DNA-treated mice were shown to secrete interferon-gamma when stimulated with either APL cells or peptides from the promyelocytic leukemia-RARalpha vaccine-derived sequences as detected by ELISpot assays. Our results demonstrate that DNA vaccination with ATRA confers the effective boosting of interferon-gamma-producing and cytotoxic T cells in the leukemic mice.
Furugaki
Kouichi
K
Inserm UMRS 940, Université Paris 7, Paris, France.
Pokorna
Katerina
K
Le Pogam
Carole
C
Aoki
Masayuki
M
Reboul
Murielle
M
Bajzik
Véronique
V
Krief
Patricia
P
Janin
Anne
A
Noguera
Marie-Elena
ME
West
Robert
R
Charron
Dominique
D
Chomienne
Christine
C
Pla
Marika
M
Moins-Teisserenc
Hélène
H
Padua
Rose Ann
RA
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects / Q000235:genetics; D015473:Leukemia, Promyelocytic, Acute / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000008:administration & dosage / Q000235:genetics; D016019:Survival Analysis; D016896:Treatment Outcome; D014212:Tretinoin / Q000008:administration & dosage*; D014407:Tumor Cells, Cultured; D019444:Vaccines, DNA / Q000008:administration & dosage* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D015514:Oncogene Proteins, Fusion; D019444:Vaccines, DNA; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D014212:Tretinoin