RESUMEN
Multiple myeloma (MM) is an incurable plasma cell cancer in the bone marrow. Immunomodulatory drugs, such as lenalidomide (LEN) and pomalidomide, are backbone agents in MM treatment, and LEN resistance is commonly seen in the MM clinic. In this study, we presented that heterogeneous nuclear ribonucleoprotein U (hnRNPU) affected MM resistance to LEN via the regulation of target mRNA translation. hnRNPULow MM cells exhibited upregulated CRBN and IKZF1 proteins, stringent IKZF1/3 protein degradation upon LEN addition and increased sensitivity to LEN. RNA pulldown assays and RNA electrophoretic mobility shift assays revealed that hnRNPU bound to the 3'-untranslated region of CRBN and IKZF1 mRNA. A sucrose gradient assay suggested that hnRNPU specifically regulated CRBN and IKZF1 mRNA translation. The competition of hnRNPU binding to its target mRNAs by small RNAs with hnRNPU-binding sites restored MM sensitivity to LEN. hnRNPU function in vivo was confirmed in an immunocompetent MM mouse model constructed by the inoculation of Crbn-humanized murine 5TGM1 cells into CrbnI391V/+ mice. Overall, this study suggests a novel mechanism of LEN sensitivity in which hnRNPU represses CRBN and IKZF1 mRNA translation.
Asunto(s)
Lenalidomida , Mieloma Múltiple , Lenalidomida/farmacología , Lenalidomida/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/genética , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patología , Humanos , Ratones , Animales , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Línea Celular Tumoral , Resistencia a Antineoplásicos/genética , Factor de Transcripción Ikaros/genética , Factor de Transcripción Ikaros/metabolismoRESUMEN
Aggrephagy, a type of autophagy, degrades the aggregation of misfolded protein in cells. However, the role of aggrephagy in multiple myeloma (MM) has not been fully demonstrated. In this study, we first investigated the correlation between aggrephagy signaling, MM immune microenvironment composition and disease prognosis. Single-cell RNA-seq data, including the expression profiles of 12,187 single cells from seven MM bone marrow (BM) and seven healthy BM samples, were analyzed by non-negative matrix factorization for 44 aggrephagy-related genes. Bulk RNA-seq cohorts from the Gene Expression Omnibus database were used to evaluate the prognostic value of aggrephagy-related immune cell subtypes and predict immune checkpoint blockade immunotherapeutic response in MM. Compared with healthy BM, MM BM exhibited different patterns of aggrephagy-related gene expression. In MM BM, macrophages, CD8+ T cells, B cells and natural killer cells could be grouped into four to nine aggrephagy-related subclusters. The signature of aggrephagy signaling molecule expression in the immune cells correlates with the patient's prognosis. Our investigation provides a novel view of aggrephagy signaling in MM tumor microenvironment cells, which might be a prognostic indicator and potential target for MM treatment.
Asunto(s)
Mieloma Múltiple , Transducción de Señal , Análisis de la Célula Individual , Microambiente Tumoral , Mieloma Múltiple/genética , Mieloma Múltiple/inmunología , Humanos , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Análisis de la Célula Individual/métodos , Pronóstico , Regulación Neoplásica de la Expresión Génica , Autofagia/genética , Autofagia/inmunología , Perfilación de la Expresión Génica/métodos , Biomarcadores de Tumor/genética , TranscriptomaRESUMEN
Multiple myeloma(MM)is a systemic malignancy of plasma cells.Nowadays,the basic research on MM is flourishing with the continuous optimization and innovation of mouse models of MM.Heterologous mouse models of MM established with human-derived cells and immunodeficient mice have been applied in assessing drug efficacy,exploring drug resistance mechanisms,and observing tumor-bone marrow microenvironment interactions.In the last decades,the homologous mouse models of MM established with murine-derived cells or gene-editing technologies have been widely used in the research on the pathogenesis and drug development.Additionally,the stable modeling of targeted organ injury will be a key problem to be tackled in this field.This review summarizes the characteristics and application progress of mouse models of MM.
Asunto(s)
Mieloma Múltiple , Humanos , Animales , Ratones , Mieloma Múltiple/patología , Médula Ósea/patología , Modelos Animales de Enfermedad , Resistencia a Medicamentos , Microambiente TumoralRESUMEN
Although the development of novel drugs has significantly improved the survival of patients with multiple myeloma (MM) over the past decades,the lack of effective therapeutic options for relapsed and refractory MM results in poor prognosis.The chimeric antigen receptor (CAR) T-cell therapy has achieved considerable progress in relapsed and refractory MM.Nevertheless,this therapy still has limitations such as cytokine release syndrome,neurotoxicity,and off-target effects.Natural killer (NK) cells,as a critical component of the innate immune system,play an essential role in tumor immunosurveillance.Therefore,CAR-modified NK (CAR-NK) cells are put forward as a therapeutic option for MM.The available studies have suggested that multiple targets can be used as specific therapeutic targets for CAR-NK cell therapy and confirmed their antitumor effects in MM cell lines and animal models.This review summarizes the anti-tumor mechanisms,biological characteristics,and dysfunction of NK cells in the MM tumor microenvironment,as well as the basic and clinical research progress of CAR-NK cells in treating MM.
Asunto(s)
Mieloma Múltiple , Receptores Quiméricos de Antígenos , Animales , Receptores Quiméricos de Antígenos/metabolismo , Mieloma Múltiple/terapia , Mieloma Múltiple/metabolismo , Células Asesinas Naturales/metabolismo , Inmunoterapia Adoptiva/métodos , Microambiente TumoralRESUMEN
Exosomal microRNAs (miRNAs) are potential biomarkers for a variety of tumors, but have not yet been studied in diffuse large B-cell lymphoma (DLBCL). Here, we investigated the use of exosomal miRNAs in DLBCL diagnosis and prognosis. A total of 256 individuals, including 133 DLBCL patients, 94 healthy controls (HCs), and 29 non-DLBCL concurrent controls (CCs), were enrolled. Exosomal miRNAs were profiled in the screening stage using microarray analysis, and miRNA candidates were confirmed in training, testing, and external testing stages using qRT-PCR. Follow-up information on the DLBCL patients was collected, and miRNAs were used to develop diagnostic and prognostic models for these patients. Five exosomal miRNAs (miR-379-5p, miR-135a-3p, miR-4476, miR-483-3p, and miR-451a) were differentially expressed between DLBCL patients and HCs with areas under the receiver operating characteristic curve (AUC) of 0.86, 0.90, and 0.86 for the training, testing, and external testing stages, respectively. Four exosomal miRNAs (miR-379-5p, miR-135a-3p, miR-4476, and miR-451a) were differentially expressed between patients with DLBCL and CCs, with an AUC of 0.78. One miRNA (miR-451a) was significantly associated with both progression-free survival (PFS) and overall survival (OS) of DLBCL patients, R analysis indicated the combination of miR-451a with international prognostic index was a better predictor of PFS and OS for these patients. Our study suggests that subsets of circulating exosomal miRNAs can be useful noninvasive biomarkers for the diagnosis of DLBCL and that the use of circulating exosomal miRNAs improves the identification of patients with newly diagnosed DLBCL with poor outcomes.
Asunto(s)
Exosomas , Linfoma de Células B Grandes Difuso , MicroARNs , Biomarcadores , Biomarcadores de Tumor/genética , Humanos , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , MicroARNs/genética , PronósticoRESUMEN
PURPOSE: The aim of this study was to investigate symptom clusters and associated clinical factors in ambulatory multiple myeloma patients undergoing medication therapy. We also aimed to determine the correlations between symptom clusters and patient quality of life. METHODS: A total of 174 multiple myeloma patients hospitalized in the haematology day unit were included in this study. A cross-sectional survey was conducted to examine symptoms and quality of life. Symptoms were assessed by the Chinese version of the Condensed Memorial Symptom Assessment Scale. Quality of life was measured with the Functional Assessment of Cancer Therapy-General. Principal component analysis was used to identify symptom clusters. Independent-samples t tests and chi-square tests were used for comparisons between groups. Spearman's rank correlation analysis was used to identify correlations. RESULTS: We identified three symptom clusters in multiple myeloma patients: psychological; pain, dry mouth, and difficulty sleeping; and fatigue symptom cluster. For each symptom cluster, the patients could be categorized into a severe-symptom group or a mild-symptom group based on the distress of symptoms. The patients in each group exhibited differential demographic and clinical features. Symptom cluster distress was adversely correlated with patients' quality of life. CONCLUSIONS: Ambulatory multiple myeloma patients undergoing anticancer medication therapy experience multiple symptoms, which can be categorized into three symptom clusters. For each symptom cluster, level of distress was associated with patients' demographic and clinical characteristics. The presence and level of distress of these symptom clusters have adverse impacts on patients' quality of life.
Asunto(s)
Mieloma Múltiple , Trastornos del Sueño-Vigilia , Análisis por Conglomerados , Estudios Transversales , Humanos , Mieloma Múltiple/tratamiento farmacológico , Calidad de Vida/psicología , SíndromeRESUMEN
The aim of this study was to investigate the effect of low-dose ruxolitinib (daily dose ≤ 10 mg) for the treatment of myelofibrosis (MF). A retrospective analysis was performed on a total of 88 patients with myeloproliferative neoplasm-associated MF (MPN-MF) who were diagnosed and treated in West China Hospital, Sichuan University, China. A total of 44 MPN-MF patients received a low dose of ruxolitinib (daily dose ≤ 10 mg), while another 44 patients received 10-25 mg twice daily. Low-dose ruxolitinib treatment resulted in slow, but gradual spleen response. Compared with baseline, the mean changes in palpable spleen length in the low- and high-dose groups were -26.9 and -49.0% after 12 weeks of treatment, respectively, and -46.7 and -64.1% after 48 weeks of treatment, respectively. In the low dose group, the median myeloproliferative neoplasm symptom assessment form (MPN-SAF) total symptom score (TSS) decreased by 37.8 and 35.9% at the 12 weeks and 48 weeks after treatment, respectively. No statistical difference was observed in MPN-SAF TSS among different dose groups. After 48 weeks of treatment, bone marrow (BM) fibrosis improved in 43.3% (13/30) of evaluated patients and was stable in 56.7% (17/30) patients. In the low-dose treated group, BM fibrosis improved in 50% patients and was stable in remaining 50%. Low-dose ruxolitinib is effective in treating MF.
Asunto(s)
Inhibidores de las Cinasas Janus/administración & dosificación , Mielofibrosis Primaria/tratamiento farmacológico , Pirazoles/administración & dosificación , Bazo/efectos de los fármacos , Adulto , Anciano , Anciano de 80 o más Años , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nitrilos , Mielofibrosis Primaria/patología , Pirimidinas , Estudios Retrospectivos , Bazo/patología , Resultado del TratamientoRESUMEN
AIMS: To examine the feasibility and efficacy of self-help relaxation exercises in alleviating symptom distress in adult patients with acute leukemia (AL). METHODS: A pilot randomized controlled trial was used. Thirty adult patients with AL who were hospitalized in a teaching hospital were enrolled and randomly divided into a wait-list control group or an intervention group. The intervention group received self-help relaxation exercise twice per day for 4 weeks. The feasibility indicators, patients' symptom distress were assessed by a blinded data collector. RESULTS: Twenty-nine patients completed the study. The recruitment rate, retention rate, and adherence rate was 65.2%, 93.3%, and 98.2%, respectively. The intervention group had a significantly decreased distress score for pain symptoms (F1, 27 = 6.594, P = .016, the partial η2 = 0.20, 90% confidence interval = 0.02-0.39). CONCLUSIONS: Self-help relaxation exercises were feasible for the AL patients and significantly reduced their pain symptoms. Minor revision of the protocol for future definitive trials is needed.
Asunto(s)
Terapia por Ejercicio , Leucemia , Adulto , Ejercicio Físico , Estudios de Factibilidad , Humanos , Leucemia/complicaciones , Leucemia/terapia , Proyectos PilotoRESUMEN
To study glycolysis/glycogenesis-related genes expression in childhood B-cell acute lymphoblastic leukaemia (B-ALL), we performed a microarray-based analysis using published gene expression profiles. We found that SLC2A5, which encodes solute carrier family 2 member 5 (SLC2A5, previously termed GLUT5) that facilitates cell fructose uptake, was up-regulated in Philadelphia chromosome-positive ALL (Ph+ALL). Microarray-based analyses also suggested that SLC2A5 expression was significantly down-regulated in childhood B-ALL with t(1;19) or 11q23 mutation. High SLC2A5 expression was found in patients who had disease recurrence within 3 years, early relapse, shortened complete remission duration and positive minimal residue disease (MRD) status after treatment. SLC2A5 overexpression at both the mRNA and protein level in Ph+ALL was confirmed in a validation cohort of childhood B-ALL. We also validated the correlation of SLC2A5 expression and MRD status. A mechanistic study using a human Ph+ALL cell line showed that BCR-ABL1 kinase might regulate SLC2A5 expression via MYC. The tyrosine kinase inhibitors (TKIs) imatinib and dasatinib repressed SLC2A5 expression and the cell uptake of fructose. Fructose protected the tumour cells from nutrition deficiency and drug-induced cell death. Overall, our findings showed that SLC2A5 was up-regulated in childhood Ph+ALL. SLC2A5 expression correlated with childhood B-ALL clinical factors, such as MRD status. Given that TKIs could inhibit SLC2A5 expression, repression of fructose utility after TKI treatment contributes to TKI-induced Ph+ALL cytotoxicity. Targeting SLC2A5 might be promising in B-ALL treatment, especially for Ph+ALL patients with high SLC2A5 expression.
Asunto(s)
Transportador de Glucosa de Tipo 5/biosíntesis , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Adolescente , Niño , Preescolar , Femenino , Fructosa/metabolismo , Proteínas de Fusión bcr-abl/fisiología , Perfilación de la Expresión Génica/métodos , Regulación Leucémica de la Expresión Génica , Transportador de Glucosa de Tipo 5/genética , Humanos , Lactante , Masculino , Mutación , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , ARN Mensajero/genética , ARN Neoplásico/genética , Recurrencia , Células Tumorales Cultivadas , Regulación hacia ArribaRESUMEN
Because cytokine-priming signals direct CD8(+) T cells to acquire unique profiles that affect their ability to mediate specific immune responses, here we generated IL-9-skewed CD8(+) T (Tc9) cells by priming with Th9-polarized condition. Compared with type-I CD8(+) cytotoxic T (Tc1) cells, Tc9 secreted different cytokines and were less cytolytic in vitro but surprisingly elicited greater antitumor responses against advanced tumors in OT-I/B16-OVA and Pmel-1/B16 melanoma models. After adoptive transfer, Tc9 cells persisted longer and differentiated into IFN-γ- and granzyme-B (GrzB)-producing cytolytic Tc1-like effector cells. Phenotypic analysis revealed that adoptively transferred Tc9 cells secreted IL-2 and were KLRG-1(low) and IL-7Rα(high), suggesting that they acquired a signature of "younger" phenotype or became long-term lived cells with capacity of self-renewal. Our results also revealed that Tc9-mediated therapeutic effect critically depended on IL-9 production in vivo. These findings have clinical implications for the improvement of CD8(+) T-cell-based adoptive immunotherapy of cancers.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Inmunoterapia Adoptiva , Interleucina-9/biosíntesis , Melanoma Experimental/inmunología , Animales , Linfocitos T CD8-positivos/citología , Diferenciación Celular , Ciclofosfamida/farmacología , Citocinas/metabolismo , Ensayo de Inmunoadsorción Enzimática , Interferón gamma/biosíntesis , Melanoma Experimental/terapia , RatonesRESUMEN
Hedgehog (Hh) signaling plays an important role in the oncogenesis of B-cell malignancies such as multiple myeloma (MM). However, the source of Hh ligand sonic hedgehog (SHH) and its target cells remains controversial. Previous studies showed that stromally induced Hh signaling is essential for the tumor cells and that CD19(+)CD138(-) MM stem cells are the target cells of Hh signaling. Here we demonstrate that SHH was mainly secreted by human myeloma cells but not by stromal cells in MM bone marrow. Autocrine SHH enhanced CD138(+) myeloma cell proliferation and protected myeloma cells from spontaneous and stress-induced apoptosis. More importantly, autocrine SHH protected myeloma cells against chemotherapy-induced apoptosis in vitro and in vivo. Combinational treatment with chemotherapy and SHH-neutralizing antibody displayed synergistic antimyeloma effects. Mechanistic studies showed that SHH signaling activated the SHH/GLI1/BCL-2 axis, leading to the inhibition of myeloma cell apoptosis. Thus, this study identifies the myeloma autocrine Hh signaling pathway as a potential target for the treatment of MM. Targeting this pathway may improve the efficacy of chemotherapy in MM patients.
Asunto(s)
Comunicación Autocrina , Resistencia a Antineoplásicos , Proteínas Hedgehog/metabolismo , Mieloma Múltiple/metabolismo , Transducción de Señal , Sindecano-1/metabolismo , Animales , Antineoplásicos/farmacología , Apoptosis/genética , Biopsia , Médula Ósea/metabolismo , Médula Ósea/patología , Estudios de Casos y Controles , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular/genética , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos/genética , Femenino , Expresión Génica , Proteínas Hedgehog/genética , Humanos , Mieloma Múltiple/genética , Mieloma Múltiple/mortalidad , Mieloma Múltiple/patología , Proteínas Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Transactivadores/metabolismo , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Proteína con Dedos de Zinc GLI1RESUMEN
p38 MAPK signaling controls cell growth, proliferation and the cell cycle under stress conditions. However, the function of p38 activation in tumor metastasis is still not well understood. We report that p38 activation in breast cancer cells inhibits tumor metastasis but does not substantially modulate primary tumor growth. Stable p38 knockdown in breast cancer cells suppressed NF-κB p65 activation, inhibiting miR-365 expression and resulting in increased IL-6 secretion. The inhibitory effect of p38 signaling on metastasis was mediated by suppression of mesenchymal stem cell (MSC) migration to the primary tumor and sites of metastasis, where MSCs can differentiate into cancer-associated fibroblasts to promote tumor metastasis. The migration of MSCs to these sites relies on CXCR4-SDF1 signaling in the tumor microenvironment. Analysis of human primary and metastatic breast cancer tumors showed that p38 activation was inversely associated with IL-6 and vimentin expression. This study suggests that combination analysis of p38 MAPK and IL-6 signaling in patients with breast cancer may improve prognosis and treatment of metastatic breast cancer.
Asunto(s)
Neoplasias de la Mama/enzimología , Neoplasias Pulmonares/enzimología , Células Madre Mesenquimatosas/fisiología , Proteínas Quinasas p38 Activadas por Mitógenos/fisiología , Animales , Apoptosis , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular , Quimiocina CXCL12/metabolismo , Femenino , Fibroblastos/patología , Regulación Neoplásica de la Expresión Génica , Humanos , Interleucina-6/metabolismo , Neoplasias Pulmonares/secundario , Sistema de Señalización de MAP Quinasas , Ratones Endogámicos BALB C , MicroARNs/metabolismo , Trasplante de Neoplasias , Receptores CXCR4/metabolismo , Microambiente Tumoral , Vimentina/metabolismoRESUMEN
BACKGROUND: Interferon (IFN)-γ-mediated immune response plays an important role in tumor immunosurveillance. However, the regulation of IFN-γ-mediated tumorigenesis and immune response remains elusive. USP18, an interferon stimulating response element, regulates IFN-α-mediated signaling in anti-viral immune response, but its role in IFN-γ-mediated tumorigenesis and anti-tumor immune response is unknown. METHOD: In this study, USP18 in tumorigenesis and anti-tumor immune response was comprehensively appraised in vivo by overexpression or downregulation its expression in murine B16 melanoma tumor model in immunocompetent and immunodeficient mice. RESULTS: Ectopic expression or downregulation of USP18 in B16 melanoma tumor cells inhibited or promoted tumorigenesis, respectively, in immunocompetent mice. USP18 expression in B16 melanoma tumor cells regulated IFN-γ-mediated immunoediting, including upregulating MHC class-I expression, reducing tumor cell-mediated inhibition of T cell proliferation and activation, and suppressing PD-1 expression in CD4+ and CD8+ T cells in tumor-bearing mice. USP18 expression in B16 melanoma tumor cells also enhanced CTL activity during adoptive immunotherapy by prolonging the persistence and enhancing the activity of adoptively transferred CTLs and by reducing CTL exhaustion in the tumor microenvironment. Mechanistic studies demonstrated that USP18 suppressed tumor cell-mediated immune inhibition by activating T cells, inhibiting T-cell exhaustion, and reducing dendritic cell tolerance, thus sensitizing tumor cells to immunosurveillance and immunotherapy. CONCLUSION: These findings suggest that stimulating USP18 is a feasible approach to induce B16 melanoma specific immune response.
Asunto(s)
Carcinogénesis/inmunología , Regulación Neoplásica de la Expresión Génica/inmunología , Interferón gamma/inmunología , Melanoma Experimental/inmunología , Neoplasias Cutáneas/inmunología , Ubiquitina Tiolesterasa/inmunología , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/patología , Carcinogénesis/genética , Carcinogénesis/patología , Proliferación Celular , Citotoxicidad Inmunológica , Células Dendríticas/inmunología , Células Dendríticas/patología , Femenino , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase I/inmunología , Inmunidad Innata , Inmunoterapia Adoptiva , Interferón gamma/genética , Melanoma Experimental/genética , Melanoma Experimental/patología , Ratones , Ratones Endogámicos C57BL , Ratones SCID , Trasplante de Neoplasias , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/inmunología , Transducción de Señal , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/patología , Linfocitos T Citotóxicos/trasplante , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Ubiquitina Tiolesterasa/genéticaRESUMEN
Our previous studies showed that anti-ß2M monoclonal antibodies (mAbs) at high doses have direct apoptotic effects on myeloma cells, suggesting that anti-ß2M mAbs might be developed as a novel therapeutic agent. In this study, we investigated the ability of the mAbs at much lower concentrations to indirectly kill myeloma cells by utilizing immune effector cells or molecules. Our results showed that anti-ß2M mAbs effectively lysed MM cells via antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), which were correlated with and dependent on the surface expression of ß2M on MM cells. The presence of MM bone marrow stromal cells or addition of IL-6 did not attenuate anti-ß2M mAb-induced ADCC and CDC activities against MM cells. Furthermore, anti-ß2M mAbs only showed limited cytotoxicity toward normal B cells and nontumorous mesenchymal stem cells, indicating that the ADCC and CDC activities of the anti-ß2M mAbs were more prone to the tumor cells. Lenalidomide potentiated in vitro ADCC activity against MM cells and in vivo tumor inhibition capacity induced by the anti-ß2M mAbs by enhancing the activity of NK cells. These results support clinical development of anti-ß2M mAbs, both as a monotherapy and in combination with lenalidomide, to improve MM patient outcome.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Citotoxicidad Celular Dependiente de Anticuerpos/inmunología , Apoptosis/inmunología , Mieloma Múltiple/terapia , Microglobulina beta-2/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Antígenos de Superficie/inmunología , Proliferación Celular , Proteínas del Sistema Complemento/inmunología , Humanos , Factores Inmunológicos/farmacología , Interleucina-6/inmunología , Lenalidomida , Masculino , Células Madre Mesenquimatosas/inmunología , Ratones , Ratones SCID , Mieloma Múltiple/inmunología , Interferencia de ARN , ARN Interferente Pequeño , Talidomida/análogos & derivados , Talidomida/farmacología , Resultado del Tratamiento , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto , Microglobulina beta-2/antagonistas & inhibidores , Microglobulina beta-2/genéticaRESUMEN
Dendritic cells (DCs) are professional antigen-presenting cells to initiate immune responses, and DC survival time is important for affecting the strength of T-cell responses. Interleukin (IL)-9-producing T-helper (Th)-9 cells play an important role in anti-tumor immunity. However, it is unclear how Th9 cells communicate with DCs. In this study, we investigated whether murine Th9 cells affected the survival of myeloid DCs. DCs derived from bone marrow of C57BL/6 mice were cocultured with Th9 cells from OT-II mice using transwell, and the survival of DCs was examined. DCs cocultured with Th9 cells had longer survival and fewer apoptotic cells than DCs cultured alone in vitro. In melanoma B16-OVA tumor-bearing mice, DCs conditioned by Th9 cells lived longer and induced stronger anti-tumor response than control DCs did in vivo. Mechanistic studies revealed that IL-3 but not IL-9 secreted by Th9 cells was responsible for the prolonged survival of DCs. IL-3 upregulated the expression of anti-apoptotic protein Bcl-xL and activated p38, ERK and STAT5 signaling pathways in DCs. Taken together, our data provide the first evidence that Th9 cells can promote the survival of DCs through IL-3, and will be helpful for designing Th9 cell immunotherapy and more effective DC vaccine for human cancers.
Asunto(s)
Células Dendríticas/inmunología , Inmunoterapia Adoptiva/métodos , Interleucina-9/inmunología , Melanoma Experimental/terapia , Linfocitos T Colaboradores-Inductores/inmunología , Animales , Comunicación Celular/inmunología , Diferenciación Celular/inmunología , Supervivencia Celular/inmunología , Técnicas de Cocultivo , Células Dendríticas/citología , Humanos , Interleucina-3/biosíntesis , Interleucina-3/inmunología , Masculino , Melanoma Experimental/inmunología , Ratones , Ratones Endogámicos C57BL , Transducción de Señal , Linfocitos T Colaboradores-Inductores/citologíaRESUMEN
Dickkopf-1 (DKK1), broadly expressed in myeloma cells but highly restricted in normal tissues, together with its functional roles as an osteoblast formation inhibitor, may be an ideal target for immunotherapy in myeloma. Our previous studies have shown that DKK1 (peptide)-specific CTLs can effectively lyse primary myeloma cells in vitro. The goal of this study was to examine whether DKK1 can be used as a tumor vaccine to elicit DKK1-specific immunity that can control myeloma growth or even eradicate established myeloma in vivo. We used DKK1-DNA vaccine in the murine MOPC-21 myeloma model, and the results clearly showed that active vaccination using the DKK1 vaccine not only was able to protect mice from developing myeloma, but it was also therapeutic against established myeloma. Furthermore, the addition of CpG as an adjuvant, or injection of B7H1-blocking or OX40-agonist Abs, further enhanced the therapeutic effects of the vaccine. Mechanistic studies revealed that DKK1 vaccine elicited a strong DKK1- and tumor-specific CD4+ and CD8+ immune responses, and treatment with B7H1 or OX40 Abs significantly reduced the numbers of IL-10-expressing and Foxp3+ regulatory T cells in vaccinated mice. Thus, our studies provide strong rationale for targeting DKK1 for immunotherapy of myeloma patients.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Vacunas contra el Cáncer/uso terapéutico , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/inmunología , Mieloma Múltiple/inmunología , Mieloma Múltiple/terapia , Vacunas de ADN/uso terapéutico , Animales , Anticuerpos Monoclonales/farmacología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Femenino , Factores de Transcripción Forkhead/metabolismo , Inmunoterapia , Interleucina-10/metabolismo , Depleción Linfocítica , Ratones , Ratones Endogámicos BALB C , Mieloma Múltiple/patología , Receptores OX40/antagonistas & inhibidores , Receptores OX40/inmunología , Receptores OX40/metabolismo , Linfocitos T Citotóxicos/inmunología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/patología , Células Tumorales Cultivadas , VacunaciónRESUMEN
Background: Acute myeloid leukemia (AML) is a hematological malignancy with poor patient prognosis. Cuprotosis is a newly discovered cell death that regulates the proliferation and progression of tumor cells. Long non-coding RNAs (lncRNAs) are key molecules and potential biomarkers for the diagnosis and treatment of various diseases. However, the effect of cuprotosis-associated lncRNAs on AML remains unclear. Objective: The aim of this study was to investigate the relationship between the expression of cuprotosis-related gene and the prognosis of AML. Methods: Consensus cluster analysis was performed on AML patients according to the cuprotosis-related gene expression matrix, and survival analysis and differential gene analysis were performed. Then lncRNA and miRNA related to AML tumor progression were screened according to univariate COX regression analysis. After that, Kaplan-Meier analysis, correlation analysis, and AUC curve were used to determine the ceRNA network that might regulate AML. The regulatory relationship of ceRNA was verified in AML cell lines by RT-qPCR and Western blotting. Results: The AC024896.1/miR-363-3p axis drives MYO1B to promote the malignant progression of AML. First, a change in the expression of AC024896.1 and miR-363-3p can affect the proliferation of AML by regulating MYO1B. Mechanistically, AC024896.1 regulates the expression of MYO1B as the ceRNA of miR-363-3p. Moreover, the regulation of AC024896.1 in the malignant progression of AML depends partly on miR-363-3p. Conclusion: In summary, our study reveals AC024896.1/miR-363-3p/MYO1B Axis in AML, which can be regarded as a new potential target for the diagnosis and treatment of AML.
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Background: Since no randomized controlled trials have directly compared the efficacy and safety of immunotherapy with daratumumab versus lenalidomide/bortezomib/dexamethasone (RVD) in the frontline treatment of transplant-ineligible newly diagnosed multiple myeloma (TIE-NDMM), this study systematically reviewed the clinical studies regarding immunotherapy with daratumumab and RVD regimen in the treatment of TIE-NDMM to explore the optimization direction of the best first-line therapy. Methods: The Cochrane Library, PubMed, Embase, and Web of Science databases were searched to collect studies on regimens containing daratumumab or RVD/RVD-lite for TIE-NDMM. Pooled and meta-analysis was then performed to compare the overall response rate (ORR), stringent complete remission (sCR) and CR rate, progression-free survival (PFS), overall survival (OS) and treatment-related discontinuation rate between daratumumab-containing immunotherapy regimen and RVD/RVD-lite regimen by using R 4.3.1 software. Results: Nine prospective clinical trials were included, including 1795 TIE-NDMM or NDMM without intent for immediate ASCT. Among them, 938 patients were treated with daratumumab-based immunotherapy and 857 with RVD/RVD-lite regimens. Meta-analysis results showed that The daratumumab-based regimen showed a significantly higher CR/sCR rate than RVD/RVD-lite for TIE-NDMM (47% vs. 24%, P<0.01). The median PFS of the daratumumab-based and RVD/RVD-lite groups were 52.6 months and 35.1 months respectively (HR 0.77, 95%CI, 0.66-0.90). The median OS of both groups was not reached, and there were no significant differences in OS between the two groups (HR 1.03, 95%CI, 0.86-1.23). The therapy discontinuation rate led by adverse events was significantly higher in the RVD/RVD-lite group than in the daratumumab-based regimen group for the TIE-NDMM (16% vs. 7%, P=0.03). Conclusion: This meta-analysis suggests that daratumumab-containing immunotherapy is superior to RVD in the depth of treatment efficacy, progression-free survival, and lower treatment-related discontinuation rates. Limited by the lack of head-to-head clinical trials, this conclusion needs to be verified by concurrent cohort studies.
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Although the significant strides in novel therapeutic approaches have prolonged the survival of multiple myeloma (MM) patients, the unfavorable prognosis of cytogenetically high-risk newly diagnosed MM (NDMM) remains intractable with the lack of consensus regarding the choice of maintenance regimens. Therefore, this study was initiated with the aim of examining the effectiveness of various maintenance treatments for this group of patients in jeopardy. Overall, 17 studies with 1937 high-risk NDMM patients were included in the network meta-analysis. Combination therapies involving novel drugs presented encouraging prospects in the maintenance phase, while the patients and circumstances for the application of different regimens still needed to be further distinguished and clarified. To investigate the current status of maintenance therapy of high-risk NDMM patients in clinical practice, a real-world cohort of high-risk NDMM was retrospectively incorporated 80 patients with lenalidomide maintenance and 53 patients with bortezomib maintenance, presenting the median PFS of 31.7 months and 30.4 months, respectively (p = 0.874, HR = 0.966, 95% CI: 0.628-1.486). Collectively, this study illuminated the present constraints of conventional approaches during the maintenance phase for high-risk NDMM patients while highlighting the future potential associated with enhanced regimens integrating novel medications.
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Lenalidomida , Quimioterapia de Mantención , Mieloma Múltiple , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/genética , Humanos , Lenalidomida/uso terapéutico , Bortezomib/uso terapéutico , Masculino , Femenino , Persona de Mediana Edad , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Estudios Retrospectivos , Antineoplásicos/uso terapéutico , Resultado del TratamientoRESUMEN
Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of non-Hodgkin lymphoma. Patients with hemophagocytic lymphohistiocytosis (HLH)-associated IVLBCL variants exhibit significantly poor survival. Cytokines play pivotal roles in malignancy-associated HLH as well as in capillary leak syndrome (CLS). The pathogenesis of CLS involves hyperpermeability and transient endothelial dysfunction. Here, we report the first case of HLH-associated IVLBCL variant complicated with CLS. The patient presented with fever, refractory hypoproteinemia, hypotension and severe edema, followed by telangiectasias. Treatment with etoposide and dexamethasone and hydroxyethyl starch-based artificial colloid led to transient improvement. The diagnosis of IVLBCL was confirmed after the sixth bone marrow biopsy. Subsequently, the R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisolone) regimen was administered and resulted in prompt alleviation of CLS and HLH symptoms. The patient has survived for more than 6 years after combination of immunochemotherapy and autologous peripheral stem-cell transplantation. This case provides some insights into the mechanism and clinical management of IVLBCL complicated with HLH and CLS. Similar cases concerning lymphoma-associated CLSs were also reviewed.