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

• Published in: Blood Vol. 115; no. 3; pp. 653 - 656
• Main Authors: Furugaki, Kouichi, Pokorna, Katerina, Le Pogam, Carole, Aoki, Masayuki, Reboul, Murielle, Bajzik, Véronique, Krief, Patricia, Janin, Anne, Noguera, Marie-Elena, West, Robert, Charron, Dominique, Chomienne, Christine, Pla, Marika, Moins-Teisserenc, Hélène, Padua, Rose Ann
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 21.01.2010; Americain Society of Hematology
• Subjects: Animals; Biological and medical sciences; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - pathology; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - pathology; Combined Modality Therapy; Disease Models, Animal; Hematologic and hematopoietic diseases; Humans; Immunity, Cellular - drug effects; Immunity, Cellular - genetics; Leukemia, Promyelocytic, Acute - immunology; Leukemia, Promyelocytic, Acute - pathology; Leukemia, Promyelocytic, Acute - therapy; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphocyte Activation - drug effects; Lymphocyte Activation - genetics; Medical sciences; Mice; Oncogene Proteins, Fusion - administration & dosage; Oncogene Proteins, Fusion - genetics; Survival Analysis; Treatment Outcome; Tretinoin - administration & dosage; Tumor Cells, Cultured; Vaccines, DNA - administration & dosage; Vaccines, DNA - metabolism; Xenograft Model Antitumor Assays; Antineoplastic agent; Promyelocytic leukemia; Animal model; CD4 T lymphocyte; Immune response; Hematology; Acute; Rodentia; Retinoid; Malignant hemopathy; Genetic vaccine; Long term; Survival; Vertebrata; Mammalia; Treatment; Mouse; Cancer; M3 acute myelocytic leukemia; CD8 T lymphocyte; Tretinoin
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2007-08-109009

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-γ when stimulated with either APL cells or peptides from the promyelocytic leukemia-RARα vaccine-derived sequences as detected by ELISpot assays. Our results demonstrate that DNA vaccination with ATRA confers the effective boosting of interferon-γ–producing and cytotoxic T cells in the leukemic mice.