RESUMO
Adult T-cell leukemia/lymphoma (ATLL) patients have an extremely poor prognosis, partly due to their immunosuppressive state. The majority of ATLL patients have leukemic cells with phenotype similar to Tregs, prompting suggestions that ATLL cells themselves have immunosuppressive functions. In this study, we detected CD39 expression on ATLL cells, particularly frequent on aggressive subtypes. CD39 and CD73 convert extracellular adenosine triphosphate (ATP) into adenosine, a key player in Tregs' immunosuppression. In vitro culture, both CD39+ ATLL cells and normal Tregs converted rapidly extracellular ATP to AMP, which was disturbed by CD39 inhibitors, and was negated in the CD39 knockout MJ cell line. The proliferation of cocultured CD4+/CD8+ normal T cells was suppressed by CD39+ MJ cells, but not by CD39 knockout MJ cells. Supplemented ATP was exhausted by an EG7-OVA T-cell line with stable CD39 induction, but not by mock. When these cell lines were subcutaneously transplanted into murine flanks, Poly(I:C) peritoneal administration reduced tumor size to 1/3 in mock-transplanted tumors, but not in CD39 induced tumors. Overall, we found that ATLL cells express CD39 at a high rate, and our results suggest that this helps ATLL cells escape antitumor immunity through the extracellular ATPDase-Adenosine cascade. These findings will guide future clinical strategies for ATLL treatment.
Assuntos
Antígenos CD/genética , Apirase/genética , Regulação Leucêmica da Expressão Gênica , Tolerância Imunológica/genética , Imunomodulação/genética , Leucemia-Linfoma de Células T do Adulto/genética , Leucemia-Linfoma de Células T do Adulto/imunologia , Trifosfato de Adenosina/metabolismo , Animais , Antígenos CD/metabolismo , Apirase/metabolismo , Biomarcadores , Linhagem Celular Tumoral , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Xenoenxertos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunofenotipagem , Leucemia-Linfoma de Células T do Adulto/diagnóstico , Leucemia-Linfoma de Células T do Adulto/metabolismo , Camundongos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologiaRESUMO
Adult T-cell leukemia (ATL) is caused by human T-cell lymphotropic virus I (HTLV-1) and is an aggressive malignancy of CD4, CD25-expressing leukemia, and lymphoma cells. There is no accepted curative therapy for ATL. Depsipeptide, a histone deacetylase inhibitor, has demonstrated major antitumor effects in leukemias and lymphomas. In this study, we investigated the therapeutic efficacy of depsipeptide alone and in combination with daclizumab (humanized anti-Tac) in a murine model of human ATL. The Met-1 ATL model was established by intraperitoneal injection of ex vivo leukemic cells into nonobese diabetic/severe combined immunodeficiency mice. Either depsipeptide, given at 0.5 mg/kg every other day for 2 weeks, or daclizumab, given at 100 microg weekly for 4 weeks, inhibited tumor growth as monitored by serum levels of soluble IL-2R-alpha (sIL-2R-alpha) and soluble beta2-microglobulin (beta2mu) (P < .001), and prolonged survival of the leukemia-bearing mice (P < .001) compared with the control group. Combination of depsipeptide with daclizumab enhanced the antitumor effect, as shown by both sIL-2R-alpha and beta2mu levels and survival of the leukemia-bearing mice, compared with those in the depsipeptide or daclizumab alone groups (P < .001). The significantly improved therapeutic efficacy by combining depsipeptide with daclizumab supports a clinical trial of this combination in the treatment of ATL.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Depsipeptídeos/uso terapêutico , Modelos Animais de Doenças , Imunoglobulina G/uso terapêutico , Imunossupressores/uso terapêutico , Subunidade alfa de Receptor de Interleucina-2/imunologia , Leucemia-Linfoma de Células T do Adulto/tratamento farmacológico , Acetilação , Animais , Anexina A5/metabolismo , Anticorpos Monoclonais Humanizados , Apoptose/efeitos dos fármacos , Western Blotting , Caspase 3/metabolismo , Caspase 9/metabolismo , Proliferação de Células/efeitos dos fármacos , Daclizumabe , Avaliação Pré-Clínica de Medicamentos , Quimioterapia Combinada , Histonas/metabolismo , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Leucemia-Linfoma de Células T do Adulto/imunologia , Leucemia-Linfoma de Células T do Adulto/patologia , Dose Máxima Tolerável , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Receptores de Interleucina-2/imunologia , Taxa de SobrevidaRESUMO
Three adult T-cell leukemia/lymphoma-derived cell lines, MT-2, MJ, and HUT102, were investigated to determine how they responded to hyperthermia, lymphokine-activated killer (LAK) cells, or a combination of both in vitro. All three cell lines showed a similar sensitivity to LAK cells, but revealed varying degrees of sensitivity to hyperthermia (MT-2 < MJ < HUT102) by 51Cr release assay. Hyperthermia did not cause immediate cell death as determined by the trypan blue exclusion test, but did cause substantial decreases in the numbers of heated cells within 2 days. The density of the cells began to increase thereafter, which was consistent with the results of the experiments labeling the cells with 3H-TdR after hyperthermia. When the cells were heated at 39-43 degrees C for 1-3 hr and then interacted with various LAK cell/ATL cell (E/T) ratios at 37 degrees C for 4 hr, total cytolysis of the cells increased in a synergistic and/or additive manner over that of the cells without hyperthermia. Prolonged incubation of the cells at high temperature did not necessarily cause a large increase in the interaction of LAK cells after hyperthermia. This augmentation of cytolysis by LAK cells after hyperthermia was not seen in normal peripheral lymphocytes. These results suggest that the combination therapy of hyperthermia and LAK cells may be more specific, useful, and effective for treating malignant lymphoma.