RESUMO
BLT1 is a high-affinity receptor for leukotriene B4 (LTB4) that is a potent lipid chemoattractant for myeloid leukocytes. The role of LTB4/BLT1 axis in tumor immunology, including cytokine-based tumor vaccine, however, remains unknown. We here demonstrated that BLT1-deficient mice rejected subcutaneous tumor challenge of GM-CSF gene-transduced WEHI3B (WGM) leukemia cells (KO/WGM) and elicited robust antitumor responses against second tumor challenge with WEHI3B cells. During GM-CSF-induced tumor regression, the defective LTB4/BLT1 signaling significantly reduced tumor-infiltrating myeloid-derived suppressor cells, increased the maturation status of dendritic cells in tumor tissues, enhanced their CD4(+) T-cell stimulation capacity and migration rate of dendritic cells that had phagocytosed tumor-associated antigens into tumor-draining lymph nodes, suggesting a positive impact on GM-CSF-sensitized innate immunity. Furthermore, KO/WGM mice displayed activated adaptive immunity by attenuating regulatory CD4(+) T subsets and increasing numbers of Th17 and memory CD44(hi)CD4(+) T subsets, both of which elicited superior antitumor effects as evidenced by adoptive cell transfer. In vivo depletion assays also revealed that CD4(+) T cells were the main effectors of the persistent antitumor immunity. Our data collectively underscore a negative role of LTB4/BLT1 signaling in effective generation and maintenance of GM-CSF-induced antitumor memory CD4(+) T cells.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Leucemia Experimental/imunologia , Receptores do Leucotrieno B4/imunologia , Transdução de Sinais/imunologia , Imunidade Adaptativa , Transferência Adotiva , Animais , Linfócitos T CD4-Positivos/patologia , Diferenciação Celular , Linhagem Celular Tumoral , Movimento Celular , Células Dendríticas/imunologia , Células Dendríticas/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Imunidade Inata , Memória Imunológica , Leucemia Experimental/genética , Leucemia Experimental/patologia , Leucotrieno B4/imunologia , Leucotrieno B4/metabolismo , Ativação Linfocitária , Masculino , Camundongos , Camundongos Knockout , Receptores do Leucotrieno B4/deficiência , Receptores do Leucotrieno B4/genética , Transdução de Sinais/genética , Transdução GenéticaAssuntos
Antígenos de Neoplasias , Vacinas Anticâncer , Imunoterapia , Neoplasias/terapia , Vacinas de Subunidades Antigênicas , Animais , Ensaios Clínicos como Assunto , Ciclofosfamida , Humanos , Imunoterapia/métodos , Interleucina-2/administração & dosagem , Camundongos , Análise de Sequência com Séries de Oligonucleotídeos , Linfócitos T ReguladoresRESUMO
We describe two cases of Fabry disease in non-blood-related Japanese men, manifesting recurrent stroke even after the start of enzyme replacement therapy. Both exhibited chronic inflammation and ocular involvement with elevated levels of serum C reactive protein prior to the onset of stroke. We, therefore, suggest the association among persistent inflammation, ocular involvement and recurrent stroke in a certain subset of Fabry disease patients. Both cases received enzyme replacement therapy with no improvement in inflammatory signs or laboratory data. These cases suggest that Fabry disease should be considered in young patients with cryptogenic stroke or CNS manifestations and fever of unknown origin.