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1.
Cytotherapy ; 22(7): 369-376, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32303428

RESUMEN

BACKGROUND: Qualitative and quantitative defects in natural killer (NK) cells have been noted in patients with acute myeloid leukemia (AML), providing rationale for infusion of donor-derived NK cells. We previously showed that decitabine enhances expression of NKG2D ligands in AML with additive cytotoxicity when NK cells and Fc (fragment crystallizable region)-engineered CD33 monoclonal antibody (CD33mAb) was used. We conducted a phase 1 study evaluating decitabine and haploidentical NK cells in relapsed AML. Using patient samples from this study, we evaluated whether ex vivo donor-derived expanded NK cells with or without CD33mAb was effective in decitabine-treated AML. METHODS: Bone marrow aspirates were collected from patients at pre- and post-NK cell infusion. NK cells from healthy donors were expanded for 14 days using irradiated K562 feeder cells displaying membrane-bound IL-21 (mbIL-21). Patient samples were used to test in vitro activity of mbIL-21 NK cells ± CD33m Ab-dependent cellular cytotoxicity (ADCC) and AML patient derived xenograft (PDX) mice were developed to test in vivo activity. RESULTS: Upon incubation with primary AML blasts, mbIL-21 NK cells showed variable donor-dependent intra-cellular interferon-γ production, which increased with CD33mAb-coated AML. ADCC assays revealed mbIL-21 NK cells effectively lysed primary AML blasts with higher activity on CD33mAb-coated AML. Importantly, CD33mAb-dependent enhanced cytotoxicity by mbIL-21 NK cells was maintained in AML cells from patients even 24 days post-decitabine treatment. In vivo infusion of mbIL-21 NK cells in AML PDX mice, treated with CD33mAb, reduced the tumor burden. DISCUSSION: These data show the therapeutic utility of mbIL-21 NK cells that can be further potentiated by addition of CD33mAb in AML.


Asunto(s)
Anticuerpos Monoclonales/farmacología , Membrana Celular/metabolismo , Citotoxicidad Inmunológica/efectos de los fármacos , Fragmentos Fc de Inmunoglobulinas/metabolismo , Interleucinas/metabolismo , Células Asesinas Naturales/inmunología , Leucemia Mieloide Aguda/inmunología , Lectina 3 Similar a Ig de Unión al Ácido Siálico/metabolismo , Anciano , Animales , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos Inmunológicos/farmacología , Antineoplásicos Inmunológicos/uso terapéutico , Línea Celular Tumoral , Membrana Celular/efectos de los fármacos , Femenino , Humanos , Interleucina-2/metabolismo , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/trasplante , Leucemia Mieloide Aguda/terapia , Activación de Linfocitos/efectos de los fármacos , Masculino , Ratones , Persona de Mediana Edad , Unión Proteica/efectos de los fármacos , Ingeniería de Proteínas , Vidarabina/análogos & derivados , Vidarabina/farmacología
2.
Exp Hematol ; 123: 28-33.e3, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37209901

RESUMEN

Mantle cell lymphoma (MCL) is an aggressive, noncurative, mature B-cell lymphoma, with a median overall survival of 6-7 years. This underlines a need for effective therapeutic strategies to treat MCL better. Epidermal growth factor-like 7 (EGFL7) is a protein secreted by endothelial cells shown to play a critical role in angiogenesis. Our laboratory has previously demonstrated that EGFL7 supports the growth of leukemic blasts in patients with acute myeloid leukemia (AML); however, its role in MCL has not been investigated yet. In this study, we report that EGFL7 messenger RNA (mRNA) is increased in the cells of patients with MCL compared with cells from healthy controls, and patients with high EGFL7 are associated with lower overall survival rates. Furthermore, EGFL7 is increased in the plasma of patients with MCL compared with the plasma from healthy controls. We further show that EGFL7 binds to epidermal growth factor receptor (EGFR) and activates AKT signaling pathway in MCL cells and that blocking EGFL7 in MCL in patient and cell lines decreases cell growth and increases apoptosis in vitro. Finally, anti-EGFL7 treatment inhibits tumor size and prolongs survival in a mouse model of MCL. In conclusion, our study reveals a role for EGFL7 in MCL cell proliferation and highlights EGFL7 inhibition as a promising new treatment for patients with MCL.


Asunto(s)
Linfoma de Células del Manto , Animales , Ratones , Línea Celular Tumoral , Familia de Proteínas EGF/metabolismo , Células Endoteliales/metabolismo , Linfoma de Células del Manto/metabolismo , Transducción de Señal , Humanos
3.
Int Immunol ; 23(6): 385-90, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21602176

RESUMEN

Nuclear factor I (NFI)-A is a member of the NFI family of transcription factors implicated in regulation of granulocyte differentiation. However, its role in the lymphoid lineage is not known. NFI-A deficiency results in perinatal lethality, thus precluding analysis of the role of NFI-A in lymphocyte development and function. Using recombination activation gene-2-deficient (RAG-2(-/-)) blastocysts and embryonic stem cells with homozygous NFI-A gene deletion, we show an essential role for NFI-A in T-cell activation. NFI-A(-/-)→RAG-2(-/-) chimeric mice had normal distributions of CD4(-)CD8(-) double negative, CD4(+)CD8(+) double positive, CD4(+)CD8(-) and CD4(-)CD8(+)-single positive cells in the thymus and CD4(+)CD8(-) and CD4(-)CD8(+) cells in spleen and lymph nodes. However, NFI-A(-/-)→RAG-2(-)(/)(-) mice had severely reduced thymus size and hypocellularity. The decrease in thymocytes and peripheral T cells in NFI-A(-/-)→RAG-2(-/-) chimeric mice is attributed to proliferative defects associated with decreased blast transformation, CD69 expression and DNA synthesis in response to T antigen receptor stimulation. Interestingly, NFI-A-null T cells showed increased levels of c-myc transcription that is inhibited in response to antigen receptor-mediated activation. These studies demonstrate for the first time a requirement for the NFI-A transcription factor in antigen receptor-induced T-cell activation events.


Asunto(s)
Proteínas de Unión al ADN/deficiencia , Activación de Linfocitos/genética , Factores de Transcripción NFI/metabolismo , Linfocitos T/inmunología , Animales , Ciclo Celular/inmunología , Proliferación Celular , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/inmunología , Prueba de Complementación Genética , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factores de Transcripción NFI/deficiencia , Factores de Transcripción NFI/genética , Linfocitos T/citología , Linfocitos T/metabolismo
4.
Mol Cancer Ther ; 19(4): 1018-1030, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32024684

RESUMEN

Natural killer (NK) cells play a pivotal role in controlling cancer. Multiple extracellular receptors and internal signaling nodes tightly regulate NK activation. Cyclin-dependent kinases of the mediator complex (CDK8 and CDK19) were described as a signaling intermediates in NK cells. Here, we report for the first time the development and use of CDK8/19 inhibitors to suppress phosphorylation of STAT1S727 in NK cells and to augment the production of the cytolytic molecules perforin and granzyme B (GZMB). Functionally, this resulted in enhanced NK-cell-mediated lysis of primary leukemia cells. Treatment with the CDK8/19 inhibitor BI-1347 increased the response rate and survival of mice bearing melanoma and breast cancer xenografts. In addition, CDK8/19 inhibition augmented the antitumoral activity of anti-PD-1 antibody and SMAC mimetic therapy, both agents that promote T-cell-mediated antitumor immunity. Treatment with the SMAC mimetic compound BI-8382 resulted in an increased number of NK cells infiltrating EMT6 tumors. Combination of the CDK8/19 inhibitor BI-1347, which augments the amount of degranulation enzymes, with the SMAC mimetic BI-8382 resulted in increased survival of mice carrying the EMT6 breast cancer model. The observed survival benefit was dependent on an intermittent treatment schedule of BI-1347, suggesting the importance of circumventing a hyporesponsive state of NK cells. These results suggest that CDK8/19 inhibitors can be combined with modulators of the adaptive immune system to inhibit the growth of solid tumors, independent of their activity on cancer cells, but rather through promoting NK-cell function.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Quinasa 8 Dependiente de Ciclina/antagonistas & inhibidores , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Células Asesinas Naturales/inmunología , Leucemia Mieloide Aguda/tratamiento farmacológico , Melanoma Experimental/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Animales , Apoptosis , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Proliferación Celular , Citotoxicidad Inmunológica/inmunología , Femenino , Humanos , Células Asesinas Naturales/efectos de los fármacos , Leucemia Mieloide Aguda/enzimología , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/patología , Melanoma Experimental/enzimología , Melanoma Experimental/inmunología , Melanoma Experimental/patología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones SCID , Fosforilación , Factor de Transcripción STAT1/metabolismo , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
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