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1.
Nat Commun ; 11(1): 60, 2020 01 02.
Artículo en Inglés | MEDLINE | ID: mdl-31896754

RESUMEN

Short-chain fatty acids (SCFAs) butyrate and propionate are metabolites from dietary fiber's fermentation by gut microbiota that can affect differentiation or functions of T cells, macrophages and dendritic cells. We show here that at low doses these SCFAs directly impact B cell intrinsic functions to moderately enhance class-switch DNA recombination (CSR), while decreasing at higher doses over a broad physiological range, AID and Blimp1 expression, CSR, somatic hypermutation and plasma cell differentiation. In human and mouse B cells, butyrate and propionate decrease B cell Aicda and Prdm1 by upregulating select miRNAs that target Aicda and Prdm1 mRNA-3'UTRs through inhibition of histone deacetylation (HDAC) of those miRNA host genes. By acting as HDAC inhibitors, not as energy substrates or through GPR-engagement signaling in these B cell-intrinsic processes, these SCFAs impair intestinal and systemic T-dependent and T-independent antibody responses. Their epigenetic impact on B cells extends to inhibition of autoantibody production and autoimmunity in mouse lupus models.


Asunto(s)
Anticuerpos/genética , Epigénesis Genética/efectos de los fármacos , Ácidos Grasos Volátiles/farmacología , Microbioma Gastrointestinal/inmunología , Animales , Anticuerpos/inmunología , Anticuerpos/metabolismo , Autoanticuerpos/genética , Autoanticuerpos/inmunología , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Butiratos/farmacología , Citidina Desaminasa/antagonistas & inhibidores , Citidina Desaminasa/genética , Citidina Desaminasa/inmunología , Citidina Desaminasa/metabolismo , Fibras de la Dieta , Ácidos Grasos Volátiles/aislamiento & purificación , Ácidos Grasos Volátiles/farmacocinética , Femenino , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/genética , Inhibidores de Histona Desacetilasas/inmunología , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/inmunología , Ratones Endogámicos C57BL , Ratones Mutantes , Factor 1 de Unión al Dominio 1 de Regulación Positiva/antagonistas & inhibidores , Factor 1 de Unión al Dominio 1 de Regulación Positiva/genética , Factor 1 de Unión al Dominio 1 de Regulación Positiva/inmunología , Factor 1 de Unión al Dominio 1 de Regulación Positiva/metabolismo , Propionatos/farmacología , Distribución Tisular
2.
Cancer Immunol Immunother ; 68(6): 983-990, 2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-30993371

RESUMEN

BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive skin cancer in which PD-1/PD-L1 blockade has shown remarkable response rates. However, a significant proportion of patients shows primary or secondary resistance against PD-1/PD-L1 inhibition, with HLA class-I downregulation and insufficient influx of CD8+ T cells into the tumor as possible immune escape mechanisms. Histone deacetylase inhibitors (HDACi) have been demonstrated to reverse low HLA class-I expression caused by epigenetic downregulation of the antigen machinery (APM) in vitro and in pre-clinical models in vivo. CASE PRESENTATIONS: We report four cases of patients with metastatic MCC who did not respond to immunotherapy by PD-1/PD-L1 blockade. Two of the patients received, subsequently, the HDACi panobinostat in combination with PD-1/PD-L1 blockade. Tumor biopsies of the patients were analyzed for cellular and molecular markers of antigen processing and presentation as well as the degree of T-cell infiltration. RESULTS AND CONCLUSION: Low expression of APM-related genes associated with low HLA class-I surface expression was observed in all MCC patients, progressing on PD-1/PD-L1 blockade. In one evaluable patient, of the two treated with the combination therapy of the HDACi, panobinostat and PD-1/PD-L1 blockade, reintroduction of HLA class-I-related genes, enhanced HLA class-I surface expression, and elevated CD8+ T-cell infiltration into the MCC tumor tissue were observed; however, these changes did not translate into a clinical benefit. Our findings suggest that HDACi may be useful to overcome HLA class-I downregulation as a resistance mechanism against anti-PD-1/PD-L1 antibodies in MCC patients. Prospective clinical trials are needed to evaluate this notion.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Carcinoma de Células de Merkel/tratamiento farmacológico , Antígenos de Histocompatibilidad Clase I/inmunología , Inhibidores de Histona Desacetilasas/uso terapéutico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Neoplasias Cutáneas/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/inmunología , Antígeno B7-H1/genética , Antígeno B7-H1/inmunología , Carcinoma de Células de Merkel/genética , Carcinoma de Células de Merkel/inmunología , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Regulación hacia Abajo/inmunología , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Resistencia a Antineoplásicos/inmunología , Femenino , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase I/metabolismo , Inhibidores de Histona Desacetilasas/inmunología , Humanos , Inmunoterapia/métodos , Masculino , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/inmunología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/inmunología
3.
Oncotarget ; 7(44): 71841-71855, 2016 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-27708247

RESUMEN

Non-small cell lung cancer (NSCLC), comprising 85% of lung cancer cases, has been associated with resistance to chemo/radiotherapy. The hypoxic tumor micro-environment, where insufficient vasculature results in poor drug penetrance and sub-optimal chemotherapy in the tumor interiors contributes heavily to this resistance. Additionally, epigenetic changes in tumorigenic cells also change their response to different forms of therapy. In our study, we have investigated the effectiveness of a combination of cisplatin with scriptaid [a pan-Histone Deacetylase inhibitor (HDACi)] in a model that mimics the tumor microenvironment of hypoxia and sub-lethal chemotherapy. Scriptaid synergistically increases the efficacy of cisplatin in normoxia as well as hypoxia, accompanied with reduced metastasis and enhanced DNA damage. Addition of scriptaid also overcomes the cisplatin resistance exhibited in lung cancer cells with stabilized hypoxia inducible factor 1 (HIF1)-α (mutant) and mutant p53. Molecular studies showed that the combination treatment increased apoptotic cell death in both normoxia and hypoxia with a dual role of p38MAPK. Together, our results suggest that the combination of low dose cisplatin and scriptaid is cytotoxic to NSCLC lines, can overcome hypoxia induced resistance and mutant p53- induced instability often associated with this cancer, and has the potential to be an effective therapeutic modality.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Recuento de Células , Cisplatino/farmacología , Genes p53 , Inhibidores de Histona Desacetilasas/inmunología , Hidroxilaminas/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Mutación , Quinolinas/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/genética , Línea Celular Tumoral , Cisplatino/administración & dosificación , Resistencia a Antineoplásicos , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Hidroxilaminas/administración & dosificación , Subunidad alfa del Factor 1 Inducible por Hipoxia/fisiología , Neoplasias Pulmonares/genética , Quinolinas/administración & dosificación , Microambiente Tumoral
4.
Am J Hematol ; 87(2): 226-8, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22189940

RESUMEN

Several histone deacetylase inhibitors (HDACi), including vorinostat, have been approved for the therapy of cutaneous T-cell lymphoma (CTCL). Emerging data suggest that HDACi may exert immune suppressive effects which would be disadvantageous for therapy of CTCL. We describe a patient with Sezary syndrome who was monitored for drug-induced immunosuppression while undergoing treatment with vorinostat. Analysis of the patient's natural killer cell function before and after initiation of treatment confirmed inhibition of this important cell-mediated immune function. In addition, the in vitro effects of vorinostat on the immunity of healthy volunteers confirmed that this class of drug can profoundly suppress multiple arms of the cellular immune response. These findings raise concerns of increased susceptibility to infection in this high-risk population.


Asunto(s)
Citotoxicidad Inmunológica/efectos de los fármacos , Inhibidores de Histona Desacetilasas/farmacología , Ácidos Hidroxámicos/farmacología , Inmunidad Celular/efectos de los fármacos , Células Asesinas Naturales/efectos de los fármacos , Síndrome de Sézary/tratamiento farmacológico , Anciano , Técnicas de Cocultivo , Femenino , Inhibidores de Histona Desacetilasas/inmunología , Humanos , Ácidos Hidroxámicos/inmunología , Inmunomodulación , Células K562 , Células Asesinas Naturales/inmunología , Curva ROC , Síndrome de Sézary/inmunología , Síndrome de Sézary/patología , Vorinostat
5.
Exp Toxicol Pathol ; 63(5): 511-7, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-20537879

RESUMEN

Histone deacetylases (HD) represent a novel target in cancer treatment, particularly for scattered small tumours such as the hepatocellular carcinoma (HCC). However, only few studies address the toxicological impact of HD Inhibitors (HDIs) on malignantly transformed cells versus primary hepatocytes. We examined whether and how different classes of HDIs sensitise the human HCC cell line HepG2, primary healthy murine and human liver cells towards the death receptor agonists TNFα and CD95L. Apicidin, M344 (N-hydroxy-7-(-4-dimethylaminobenzol)aminoheptanamide), CBHA (m-carboxycinnamic acid bis-hydroxamide) and VPA (valproic acid) sensitised liver cell cultures towards CD95-triggered apoptosis with the following potency: apicidin > M344 ≈ CBHA ≫ VPA. Apicidin sensitised towards CD95 also in the intact organ, i.e. in the isolated perfused mouse liver. No significant sensitisation towards TNFα was found in vitro. Western blot analysis showed that all HDIs studied downregulated the anti-apoptotic protein cFLIP, but only VPA additionally affected the expression level of XIAP. Furthermore, in models of the intrinsic apoptosis pathway, i.e. in HepG2 cells treated with Melphalan and in primary hepatocytes irradiated with UV light, only VPA exhibited significant sensitisation. These findings extend the biochemical, pharmacological and toxicological basis for HDI therapy and provide a caveat for clinical use in patients with an accompanying critical inflammatory state in which the CD95 system might be pre-activated.


Asunto(s)
Antineoplásicos/inmunología , Antineoplásicos/toxicidad , Hepatocitos/efectos de los fármacos , Inhibidores de Histona Desacetilasas/inmunología , Inhibidores de Histona Desacetilasas/toxicidad , Animales , Apoptosis/efectos de los fármacos , Apoptosis/inmunología , Western Blotting , Caspasa 3/metabolismo , Caspasa 7/metabolismo , Caspasa 8/genética , Caspasa 8/metabolismo , Técnicas de Cultivo de Célula , Supervivencia Celular/efectos de los fármacos , Proteína Ligando Fas/inmunología , Proteína Ligando Fas/metabolismo , Células Hep G2 , Hepatocitos/enzimología , Hepatocitos/inmunología , Histona Desacetilasas/metabolismo , Humanos , Hígado/efectos de los fármacos , Hígado/patología , Ratones , Ratones Endogámicos C57BL , Perfusión , Transfección , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/metabolismo
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