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1.
J Clin Endocrinol Metab ; 109(9): 2325-2334, 2024 Aug 13.
Artículo en Inglés | MEDLINE | ID: mdl-38415841

RESUMEN

CONTEXT: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with poor prognosis in advanced stages. While therapies targeting the checkpoint molecules programmed cell death 1 (PD-1), its ligand PD-L1, and the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) have revolutionized treatment in many cancers, the results in ACCs were heterogeneous. OBJECTIVE: Their expression in ACC has not been systematically studied and might explain the variable response to immune checkpoint inhibitors. METHODS: The expression of PD-1, PD-L1 and CTLA-4 was examined in 162 tumor samples from 122 patients with ACC by immunohistochemistry (threshold of >1%) and correlated with tumoral T lymphocyte infiltration and clinical endpoints. Finally, univariate and multivariate analyses of progression-free and overall survival were performed. RESULTS: PD-1 and PD-L1 were expressed in 26.5% and 24.7% of samples, respectively, with low expression in most tumor samples (median positive cells: 2.1% and 21.7%). In contrast, CTLA-4 expression was observed in 52.5% of ACC with a median of 38.4% positive cells. Positive PD-1 expression was associated with longer progression-free survival (HR 0.50, 95% CI 0.25-0.98, P = .04) even after considering prognostic factors. In contrast, PD-L1 and CTLA-4 did not correlate with clinical outcome. Additionally, PD-1 and PD-L1 expression correlated significantly with the amount of CD3+, CD4+, FoxP3+, and CD8+ T cells. CONCLUSION: The heterogeneous expression of PD1, PD-L1, and CTLA-4 in this large series of well-annotated ACC samples might explain the heterogeneous results of the immunotherapies in advanced ACC. In addition, PD-1 expression is a strong prognostic biomarker that can easily be applied in routine clinical care and histopathological assessment.


Asunto(s)
Neoplasias de la Corteza Suprarrenal , Carcinoma Corticosuprarrenal , Antígeno B7-H1 , Antígeno CTLA-4 , Receptor de Muerte Celular Programada 1 , Humanos , Antígeno CTLA-4/metabolismo , Masculino , Carcinoma Corticosuprarrenal/patología , Carcinoma Corticosuprarrenal/mortalidad , Carcinoma Corticosuprarrenal/metabolismo , Neoplasias de la Corteza Suprarrenal/mortalidad , Neoplasias de la Corteza Suprarrenal/metabolismo , Neoplasias de la Corteza Suprarrenal/patología , Neoplasias de la Corteza Suprarrenal/inmunología , Femenino , Receptor de Muerte Celular Programada 1/metabolismo , Persona de Mediana Edad , Pronóstico , Antígeno B7-H1/metabolismo , Antígeno B7-H1/análisis , Adulto , Anciano , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/análisis , Adulto Joven , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Adolescente , Anciano de 80 o más Años
2.
Surgery ; 171(1): 111-118, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34261605

RESUMEN

BACKGROUND: Immunotherapeutic response failure of adrenocortical carcinomas highlights a need for novel strategies targeting immune cell populations in the tumor microenvironment to overcome tumor resistance and enhance therapeutic response. A recent study explored a new link between tumor mast cell infiltration and improved outcomes in patients with adrenocortical carcinomas. We further dissect the role of mast cells in the tumor microenvironment of adrenocortical carcinomas by examining the tumor mast cell expression signatures and mast cell activity within the tumor microenvironment to provide additional insight into potential novel immunotherapeutic targets. METHODS: Using the CIBERSORTx computational immunogenomic deconvolution algorithm to analyze adrenocortical carcinoma tumor gene messenger RNA expression data (The Cancer Genome Atlas, N = 79), we estimated the abundance of tumor immune infiltrating mast cells and assessed prognostic potential of mast cell signaling genes as pro or antitumor signatures, as well as examined the impact on overall and disease-free survival. RESULTS: We stratified mast cell signaling genes with survival prognostic values (overall survival, disease-free survival, P < .05) into antitumor (ALOX5, CCL2, CCL5, CXCL10, HDC, IL16, TNF, TPSAB1, VEGFD) and protumor (CXCL1, CXCL3, CXCL8, IL4, IL13, PTGS3, TNSF4, VEGFD) groups. Antitumor mast cell signature, as the predominant phenotype, was associated with improved overall and disease-free survival. CONCLUSION: The deconvolution analysis of The Cancer Genome Atlas data identified mast cell infiltration in the adrenocortical carcinoma microenvironment as predominantly associated with antitumor activity. Future studies stemming from our findings may help define the role of mast cells in the tumor microenvironment and the impact on patient survival in patients with adrenocortical carcinomas. Modulation of tumor mast cell infiltration may serve as a potential target for novel synergistic immunotherapies for the treatment and improved survival of patients with adrenocortical carcinomas.


Asunto(s)
Neoplasias de la Corteza Suprarrenal/genética , Carcinoma Corticosuprarrenal/genética , Regulación Neoplásica de la Expresión Génica/inmunología , Mastocitos/inmunología , Recurrencia Local de Neoplasia/epidemiología , Corteza Suprarrenal/inmunología , Corteza Suprarrenal/patología , Neoplasias de la Corteza Suprarrenal/inmunología , Neoplasias de la Corteza Suprarrenal/mortalidad , Neoplasias de la Corteza Suprarrenal/terapia , Adrenalectomía , Carcinoma Corticosuprarrenal/inmunología , Carcinoma Corticosuprarrenal/mortalidad , Carcinoma Corticosuprarrenal/terapia , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Quimioterapia Adyuvante/métodos , Supervivencia sin Enfermedad , Sinergismo Farmacológico , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Mastocitos/metabolismo , Persona de Mediana Edad , Terapia Neoadyuvante/métodos , Pronóstico , Estudios Retrospectivos , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología
3.
J Cell Biochem ; 122(12): 1925-1935, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34581457

RESUMEN

Adrenocortical carcinoma (ACC) is a rare, but highly aggressive cancer of the adrenal cortex with a generally poor prognosis. Despite being rare, completely resected ACCs present a high risk of recurrence. Musashi-2 (MSI2) has recently been recognized as a potential prognostic biomarker and therapeutic target in many cancers. However, no studies have evaluated the clinical significance of MSI2 expression in ACC. Here, we addressed MSI2 expression and its association with ACC prognosis and clinicopathological parameters. MSI2 expression was analyzed in TCGA, GSE12368, GSE33371, and GSE49278 ACC datasets; and its correlation with other genes and immune cell infiltration were investigated by using the R2: Genomics Analysis and Visualization Platform and TIMER databases, respectively. Enrichment analysis was performed with the DAVID Functional Annotation Tool. Kaplan-Meier curves, log-rank tests, and Cox regression analyses were used to explore the prognostic role of MSI2 in ACC. Our findings demonstrated the potential value of MSI2 overexpression as an independent predictor of poor prognosis in patients with completely resected ACC (hazard ratio 6.715, 95% confidence interval 1.266 - 35.620, p =.025). In addition, MSI2 overexpression was associated with characteristics of unfavorable prognosis, such as cortisol excess (p = .002), recurrence (p =.003), and death (p =.015); positively correlated with genes related to steroid biosynthesis (p < .05); and negatively correlated with immune-related pathways (p < .05). Our findings demonstrate that MSI2 has value as a prognostic marker for completely resected ACC and reinforce the investigation of its role as a possible therapeutic target for patients with ACC.


Asunto(s)
Neoplasias de la Corteza Suprarrenal , Carcinoma Corticosuprarrenal , Biomarcadores de Tumor/inmunología , Regulación Neoplásica de la Expresión Génica/inmunología , Proteínas de Neoplasias/inmunología , Proteínas de Unión al ARN/inmunología , Neoplasias de la Corteza Suprarrenal/inmunología , Neoplasias de la Corteza Suprarrenal/mortalidad , Carcinoma Corticosuprarrenal/inmunología , Carcinoma Corticosuprarrenal/mortalidad , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esteroides/inmunología
4.
Expert Opin Emerg Drugs ; 26(2): 165-178, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33896321

RESUMEN

Introduction: Adrenocortical cancer (ACC) is a rare and aggressive disease with a median survival of 14-17 months and 5-year survival of around 20% for advanced disease. Emerging evidence of sub-groups of ACC with specific molecular drivers indicate ACC may be amenable to inhibition of receptor tyrosine kinases involved in growth and angiogenic signaling. A significant subset of patients may also be responsive to immune strategies.Areas covered: This review outlines approaches of targeting upregulated growth pathways including Insulin-like Growth Factor, Vascular Endothelial Growth Factor, Fibroblast Growth Factor and Epidermal Growth Factor Receptor in ACC. Data of immune checkpoint blockade with nivolumab, ipilimumab, pembrolizumab and avelumab is explored in detail. Genomic studies indicate that up to 40% of ACC are driven by dysregulated WNT and glucocorticoid signaling, special focus is placed on emerging drugs in these pathways.Expert opinion: Progress in the treatment of ACC has faced challenges stemming from the rarity of the disease. Given recent advances in the understanding of the molecular pathogenesis of ACC, a window of opportunity has now opened to make significant progress in developing therapeutic options that target key pathways such as excessive glucocorticoid signaling, WNT signaling, cell cycle and immune checkpoints.


Asunto(s)
Neoplasias de la Corteza Suprarrenal/tratamiento farmacológico , Carcinoma Corticosuprarrenal/tratamiento farmacológico , Antineoplásicos Inmunológicos/farmacología , Neoplasias de la Corteza Suprarrenal/inmunología , Neoplasias de la Corteza Suprarrenal/patología , Carcinoma Corticosuprarrenal/inmunología , Carcinoma Corticosuprarrenal/patología , Animales , Diseño de Fármacos , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Tasa de Supervivencia
5.
J Drugs Dermatol ; 20(1): 95-97, 2021 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-33400420

RESUMEN

Pyoderma gangrenosum (PG) is a challenging, rare, ulcerating skin disease characterized by neutrophilic abundance and absence of infection, often associated with systemic diseases. We present a 25-year old previously healthy female with a 1.5-year history of treatment refractory PG. Features of Cushing’s syndrome such as facial plethora, striae, and lipodystrophy were noted on exam, which prompted several studies that ultimately revealed an adrenal adenoma. Following surgical excision of the adenoma, symptoms rapidly resolved and systemic immunosuppressants were discontinued. This rare case highlights the importance that adrenal adenoma and resultant Cushing’s syndrome may be a driver of PG despite the pathophysiologic paradox. J Drugs Dermatol. 2021;20(1):95-97. doi:10.36849/JDD.5566.


Asunto(s)
Neoplasias de la Corteza Suprarrenal/diagnóstico , Adrenalectomía , Adenoma Corticosuprarrenal/diagnóstico , Síndrome de Cushing/diagnóstico , Piodermia Gangrenosa/inmunología , Neoplasias de la Corteza Suprarrenal/complicaciones , Neoplasias de la Corteza Suprarrenal/inmunología , Neoplasias de la Corteza Suprarrenal/cirugía , Adenoma Corticosuprarrenal/complicaciones , Adenoma Corticosuprarrenal/inmunología , Adenoma Corticosuprarrenal/cirugía , Adulto , Síndrome de Cushing/etiología , Femenino , Humanos , Inmunosupresores/uso terapéutico , Piodermia Gangrenosa/patología , Piodermia Gangrenosa/terapia , Piel/patología , Resultado del Tratamiento
6.
Int Immunopharmacol ; 88: 106930, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-32919215

RESUMEN

Emerging evidence has suggested that the tumor microenvironment, including immune infiltration, plays a crucially important role in tumor progression. Nevertheless, limited studies have been conducted on this topic in adrenocortical carcinoma. The present study aimed to explore the immune-related biomarkers in adrenocortical carcinoma. CIBERSORT was used to estimate the abundances of 22 kinds of immune cells, and univariable Cox analysis was performed to find survival-related immune cells with both Overall Survival (OS) and Progression-Free Interval (PFI). DESeq2 was applied to find differentially expressed genes between adrenocortical carcinoma and normal control samples; subsequently, weighted correlation network analysis and protein-protein interaction (PPI) network analysis were conducted to identify immune-related hub genes. xCell, TISIDB, and MsigDB were searched to validate the immune associations of hub genes. Eventually, univariable Cox and Kaplan-Meier analysis were used to assess the prognostic implications of the hub gene with the GEO database. Consequently, we identified two hub immune-related genes (ERN1, CEP55), GSEA revealed that both were mainly involved in tumor progression and immune response. ROC analysis indicated that ERN1 can accurately predict the 1-, 3-, and 5-year PFI, and CEP55 had the best performance for the prediction of both OS and PFI compared with other traits. Univariable Cox and Kaplan-Meier analysis showed that both genes have a significant effect on prognosis. Furthermore, both hub genes were validated in GEO datasets. The hub genes can provide better insights into tumor microenvironment and serve as potential biomarkers for immunotherapy in adrenocortical carcinoma.


Asunto(s)
Neoplasias de la Corteza Suprarrenal/inmunología , Carcinoma Corticosuprarrenal/inmunología , Biomarcadores de Tumor/inmunología , Microambiente Tumoral/inmunología , Neoplasias de la Corteza Suprarrenal/genética , Neoplasias de la Corteza Suprarrenal/mortalidad , Carcinoma Corticosuprarrenal/genética , Carcinoma Corticosuprarrenal/mortalidad , Adulto , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Microambiente Tumoral/genética
8.
J Surg Res ; 256: 90-95, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32683062

RESUMEN

BACKGROUND: Indoleamine 2,3-dioxygenase 1 (IDO-1) is overexpressed in many human carcinomas and a successful target for therapy in mouse models. Prognosis of patients with advanced adrenocortical carcinoma (ACC) is poor due to the lack of effective treatments, and new therapies are therefore needed. Herein, we investigate whether IDO-1 is expressed in human ACC tissues. METHODS: 53 tissue samples from patients with ACC, adrenal adenoma (AA), adrenocortical tumors (ACTs), and normal adrenal were identified. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded slides for IDO-1. Samples were scored for cytoplasmic staining as per intensity and the percent of positive cells and for stromal staining by percent of positive cells. Tumor characteristics, PD-L1, PDL-2, and CD-8+ T-lymphocyte expression were also determined. RESULTS: Samples from 32 ACC, 3 ACT, 15 AA, and 3 normal adrenal were analyzed. IDO-1 was expressed in tumor tissue in 22 of 32 ACC samples, compared with 8 of 15 AA sample (P = 0.344). IDO-1 expression was significantly increased in stromal tissue of ACC samples (16 of 33), compared with AA samples (0 of 15) (P = 0.001). IDO-1 expression in ACC and AA samples was associated with PD-L2 expression (P = 0.034). IDO-1 expression in ACC stromal tissue was associated with CD8+ T-lymphocyte infiltration (P = 0.028). CONCLUSIONS: IDO-1 is expressed in a majority of ACC samples. Its expression in tumor tissue is associated with PD-L2 expression, and expression in stroma is associated with CD8+ cell infiltration. IDO-1 inhibition, alone or in combination with PD-1 inhibition, could therefore be an interesting target in treatment of ACC.


Asunto(s)
Neoplasias de la Corteza Suprarrenal/patología , Carcinoma Corticosuprarrenal/patología , Biomarcadores de Tumor/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Corteza Suprarrenal/inmunología , Corteza Suprarrenal/patología , Neoplasias de la Corteza Suprarrenal/inmunología , Carcinoma Corticosuprarrenal/tratamiento farmacológico , Carcinoma Corticosuprarrenal/inmunología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/antagonistas & inhibidores , Biomarcadores de Tumor/inmunología , Linfocitos T CD8-positivos/inmunología , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Indolamina-Pirrol 2,3,-Dioxigenasa/análisis , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Linfocitos Infiltrantes de Tumor/inmunología , Masculino , Proteína 2 Ligando de Muerte Celular Programada 1/análisis , Proteína 2 Ligando de Muerte Celular Programada 1/inmunología , Proteína 2 Ligando de Muerte Celular Programada 1/metabolismo , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Estudios Retrospectivos
9.
J Immunother Cancer ; 8(1)2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32474412

RESUMEN

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy. Tumor-related glucocorticoid excess is present in ~60% of patients and associated with particularly poor prognosis. Results of first clinical trials using immune checkpoint inhibitors were heterogeneous. Here we characterize tumor-infiltrating T lymphocytes (TILs) in ACC in association with glucocorticoids as potential explanation for resistance to immunotherapy. METHODS: We performed immunofluorescence analysis to visualize tumor-infiltrating T cells (CD3+), T helper cells (CD3+CD4+), cytotoxic T cells (CD3+CD8+) and regulatory T cells (Tregs; CD3+CD4+FoxP3+) in 146 ACC tissue specimens (107 primary tumors, 16 local recurrences, 23 metastases). Quantitative data of immune cell infiltration were correlated with clinical data (including glucocorticoid excess). RESULTS: 86.3% of ACC specimens showed tumor infiltrating T cells (7.7 cells/high power field (HPF)), including T helper (74.0%, 6.7 cells/HPF), cytotoxic T cells (84.3%, 5.7 cells/HPF) and Tregs (49.3%, 0.8 cells/HPF). The number of TILs was associated with better overall survival (HR for death: 0.47, 95% CI 0.25 to 0.87), which was true for CD4+- and CD8+ subpopulations as well. In localized, non-metastatic ACC, the favorable impact of TILs on overall and recurrence-free survival was manifested even independently of ENSAT (European Network for the Study of Adrenal Tumors) stage, resection status and Ki67 index. T helper cells were negatively correlated with glucocorticoid excess (Phi=-0.290, p=0.009). Patients with glucocorticoid excess and low TILs had a particularly poor overall survival (27 vs. 121 months in patients with TILs without glucocorticoid excess). CONCLUSION: Glucocorticoid excess is associated with T cell depletion and unfavorable prognosis. To reactivate the immune system in ACC by checkpoint inhibitors, an inhibition of adrenal steroidogenesis might be pivotal and should be tested in prospective studies.


Asunto(s)
Neoplasias de la Corteza Suprarrenal/inmunología , Carcinoma Corticosuprarrenal/inmunología , Glucocorticoides/farmacología , Linfocitos Infiltrantes de Tumor/inmunología , Recurrencia Local de Neoplasia/inmunología , Linfocitos T Citotóxicos/inmunología , Linfocitos T Reguladores/inmunología , Adolescente , Neoplasias de la Corteza Suprarrenal/metabolismo , Neoplasias de la Corteza Suprarrenal/patología , Neoplasias de la Corteza Suprarrenal/terapia , Carcinoma Corticosuprarrenal/metabolismo , Carcinoma Corticosuprarrenal/patología , Carcinoma Corticosuprarrenal/terapia , Adulto , Anciano , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Femenino , Estudios de Seguimiento , Humanos , Inmunoterapia , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/terapia , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Reguladores/efectos de los fármacos , Adulto Joven
10.
Horm Metab Res ; 52(6): 379-385, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32168525

RESUMEN

Primary aldosteronism (PA) is the most common form of endocrine hypertension. Agonistic autoantibodies against the angiotensin II type 1 receptor (AT1R-Abs) have been described in transplantation medicine and women with pre-eclampsia and more recently in patients with PA. Any functional role of AT1R-Abs in either of the two main subtypes of PA (aldosterone-producing adenoma or bilateral adrenal hyperplasia) requires clarification. In this review, we discuss the studies performed to date on AT1R-Abs in PA.


Asunto(s)
Autoanticuerpos/fisiología , Hiperaldosteronismo/etiología , Hiperaldosteronismo/inmunología , Receptor de Angiotensina Tipo 1/inmunología , Neoplasias de la Corteza Suprarrenal/complicaciones , Neoplasias de la Corteza Suprarrenal/inmunología , Neoplasias de la Corteza Suprarrenal/metabolismo , Adenoma Corticosuprarrenal/complicaciones , Adenoma Corticosuprarrenal/inmunología , Adenoma Corticosuprarrenal/metabolismo , Aldosterona/metabolismo , Bloqueadores del Receptor Tipo 1 de Angiotensina II/metabolismo , Autoanticuerpos/metabolismo , Femenino , Humanos , Hipertensión/etiología , Hipertensión/metabolismo , Masculino , Preeclampsia/etiología , Preeclampsia/metabolismo , Embarazo
11.
J Clin Oncol ; 38(1): 71-80, 2020 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-31644329

RESUMEN

PURPOSE: Adrenocortical carcinomas (ACC) are rare and aggressive malignancies with limited treatment options. This study was undertaken to evaluate the immunogenicity of ACC. PATIENTS AND METHODS: Patients with advanced ACC were enrolled in a phase II study to evaluate the clinical activity of pembrolizumab 200 mg every 3 weeks, without restriction on prior therapy. The primary end point was objective response rate. Efficacy was correlated with tumor programmed death-ligand 1 expression, microsatellite-high and/or mismatch repair deficient (MSI-H/MMR-D) status, and somatic and germline genomic correlates. RESULTS: We enrolled 39 patients with advanced ACC and herein report after a median follow-up of 17.8 months (range, 5.4 months to 34.7 months). The objective response rate to pembrolizumab was 23% (nine patients; 95% CI, 11% to 39%), and the disease control rate was 52% (16 patients; 95% CI, 33% to 69%). The median duration of response was not reached (lower 95% CI, 4.1 months). Two of six patients with MSI-H/MMR-D tumors responded. The other seven patients with objective responses had microsatellite stable tumors. The median progression-free survival was 2.1 months (95% CI, 2.0 months to 10.7 months), and the median overall survival was 24.9 months (95% CI, 4.2 months to not reached). Thirteen percent of patients (n = 5) had treatment-related grade 3 or 4 adverse events. Tumor programmed death-ligand 1 expression and MSI-H/MMR-D status were not associated with objective response. CONCLUSION: MSI-H/MMR-D tumors, for which pembrolizumab is a standard therapy, are more common in ACC than has been recognized. In advanced ACC that is microsatellite stable, pembrolizumab provided clinically meaningful and durable antitumor activity with a manageable safety profile.


Asunto(s)
Neoplasias de la Corteza Suprarrenal/tratamiento farmacológico , Carcinoma Corticosuprarrenal/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Antineoplásicos Inmunológicos/administración & dosificación , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Neoplasias de la Corteza Suprarrenal/diagnóstico por imagen , Neoplasias de la Corteza Suprarrenal/inmunología , Carcinoma Corticosuprarrenal/diagnóstico por imagen , Carcinoma Corticosuprarrenal/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/inmunología , Tasa de Supervivencia , Adulto Joven
12.
J Clin Endocrinol Metab ; 105(1)2020 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-31513709

RESUMEN

CONTEXT: Although the development of immune checkpoint inhibitors has transformed treatment strategies of several human malignancies, research models to study immunotherapy in adrenocortical carcinoma (ACC) are lacking. OBJECTIVE: To explore the effect of anti-PD1 immunotherapy on the alteration of the immune milieu in ACC in a newly generated preclinical model and correlate with the response of the matched patient. DESIGN, SETTING, AND INTERVENTION: To characterize the CU-ACC2-M2B patient-derived xenograft in a humanized mouse model, evaluate the effect of a PD-1 inhibitor therapy, and compare it with the CU-ACC2 patient with metastatic disease. RESULTS: Characterization of the CU-ACC2-humanized cord blood-BALB/c-Rag2nullIl2rγnullSirpaNOD model confirmed ACC origin and match with the original human tumor. Treatment of the mice with pembrolizumab demonstrated significant tumor growth inhibition (60%) compared with controls, which correlated with increased tumor infiltrating lymphocyte activity, with an increase of human CD8+ T cells (P < 0.05), HLA-DR+ T cells (P < 0.05) as well as Granzyme B+ CD8+ T cells (<0.001). In parallel, treatment of the CU-ACC2 patient, who had progressive disease, demonstrated a partial response with 79% to 100% reduction in the size of target lesions, and no new sites of metastasis. Pretreatment analysis of the patient's metastatic liver lesion demonstrated abundant intratumoral CD8+ T cells by immunohistochemistry. CONCLUSIONS: Our study reports the first humanized ACC patient-derived xenograft mouse model, which may be useful to define mechanisms and biomarkers of response and resistance to immune-based therapies, to ultimately provide more personalized care for patients with ACC.


Asunto(s)
Neoplasias de la Corteza Suprarrenal/tratamiento farmacológico , Carcinoma Corticosuprarrenal/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/farmacología , Modelos Animales de Enfermedad , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Microambiente Tumoral/inmunología , Neoplasias de la Corteza Suprarrenal/inmunología , Neoplasias de la Corteza Suprarrenal/patología , Carcinoma Corticosuprarrenal/inmunología , Carcinoma Corticosuprarrenal/patología , Animales , Antineoplásicos Inmunológicos/farmacología , Apoptosis , Proliferación Celular , Femenino , Humanos , Inmunoterapia , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Receptor de Muerte Celular Programada 1/inmunología , Células Tumorales Cultivadas , Microambiente Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
13.
BMC Cancer ; 19(1): 1165, 2019 Nov 29.
Artículo en Inglés | MEDLINE | ID: mdl-31783819

RESUMEN

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare malignant endocrine tumour. Due to a high tumour recurrence rate, the post-operative overall survival (OS) and disease-free survival (DFS) of ACCs is limited. Our research aims to identify the role of the epithelial-mesenchymal transition (EMT) related genes FSCN1 and FOXM1 in the tumour microenvironment and assess their prognostic value in ACCs. METHODS: Clinical and specimen data from 130 adrenocortical carcinoma (ACC) patients was acquired from the Cancer Genome Atlas (TCGA) database (n = 79) and a West China Hospital (WCH) cohort (n = 51). In the WCH cohort, archived formalin-fixed paraffin embedded (FFPE) samples were collected for immunohistochemical analysis. The correlation between the EMT genes and the tumour microenvironment status was estimated based on the Tumour Immune Estimation Resource (TIMER) algorithm. Kaplan-Meier analysis, followed by univariate and multivariate regression analyses, were performed to identify the prognostic association of FSCN1 and FOXM1. RESULTS: FSCN1 and FOXM1 were over-expressed in ACC tissue when compared with adrenocortical adenoma and normal adrenal tissue. Over-expression of FSCN1 or FOXM1 was associated with the tumour microenvironment and immune signatures in ACCs. Patients with higher expression of FSCN1 or FOXM1 were more likely to have worse prognoses. The prognostic effects were further verified in both early (stage I/II) and advanced (stage III/IV) ACCs. Furthermore, FSCN1 and FOXM1 appeared as independent prognostic factors in ACC. CONCLUSIONS: These results show that FSCN1 and FOXM1 are independent prognostic factors in ACCs and over-expression of FSCN1 or FOXM1 indicates a worse prognosis.


Asunto(s)
Neoplasias de la Corteza Suprarrenal/patología , Carcinoma Corticosuprarrenal/patología , Proteínas Portadoras/metabolismo , Proteína Forkhead Box M1/metabolismo , Proteínas de Microfilamentos/metabolismo , Adolescente , Neoplasias de la Corteza Suprarrenal/genética , Neoplasias de la Corteza Suprarrenal/inmunología , Neoplasias de la Corteza Suprarrenal/metabolismo , Carcinoma Corticosuprarrenal/genética , Carcinoma Corticosuprarrenal/inmunología , Carcinoma Corticosuprarrenal/metabolismo , Adulto , Anciano , Biomarcadores de Tumor/metabolismo , Niño , Preescolar , Transición Epitelial-Mesenquimal/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Análisis de Supervivencia , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Regulación hacia Arriba , Adulto Joven
14.
J Immunother Cancer ; 7(1): 253, 2019 09 18.
Artículo en Inglés | MEDLINE | ID: mdl-31533818

RESUMEN

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare malignancy without good treatment options. There are limited data about the use of immunotherapy in ACC. We investigated the efficacy and safety of pembrolizumab in patients with metastatic ACC. METHODS: This is a pre-specified cohort of a single-center, investigator-initiated, phase II clinical trial using pembrolizumab monotherapy in patients with rare malignancies. Patients must have had prior treatment fail in the past 6 months before study enrollment. Patients were enrolled from August 2016 to October 2018. Follow-up data were updated as of March 26, 2019. Patients received 200 mg pembrolizumab intravenously every 3 weeks without concomitant oncologic therapy. The primary endpoint was non-progression rate (NPR) at 27 weeks. Other endpoints included adverse events, tumor responses measured independently by objective radiologic criteria, and select immunological markers. RESULTS: Sixteen patients with ACC (including eight women [50%]) were included in this cohort. Ten patients (63%) had evidence of hormonal overproduction (seven had cortisol-producing ACC). Non-progression rate at 27 weeks was evaluable in 14 patients, one patient was lost to follow-up, and one patient left the study because of an adverse event. Five of 14 patients were alive and progression-free at 27 weeks (non-progression rate at 27 weeks was 36, 95% confidence interval 13-65%). Of the 14 patients evaluable for imaging response by immune-related Response Evaluation Criteria in Solid Tumors, two had a partial response (including one with cortisol-producing ACC), seven had stable disease (including three with cortisol-producing ACC), and five had progressive disease, representing an objective response rate of 14% (95% confidence interval 2-43%). Of those who had stable disease, six had disease stabilization that lasted ≥4 months. Severe treatment-related adverse events (≥grade 3) were seen in 2 of 16 patients (13%) and resulted in one patient discontinuing study participation. All studied tumor specimens (14/14) were negative for programmed cell death ligand-1 expression. Thirteen of 14 tumor specimens (93%) were microsatellite-stable. Eight of 14 patients (57%) had a high tumor-infiltrating lymphocyte score on immunohistochemistry staining. CONCLUSIONS: Single-agent pembrolizumab has modest efficacy as a salvage therapy in ACC regardless of the tumor's hormonal function, microsatellite instability status, or programmed cell death ligand-1 status. Treatment was well tolerated in most study participants, with a low rate of severe adverse events. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02721732 , Registered March 29, 2016.


Asunto(s)
Neoplasias de la Corteza Suprarrenal/tratamiento farmacológico , Carcinoma Corticosuprarrenal/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Antineoplásicos Inmunológicos/administración & dosificación , Terapia Recuperativa/métodos , Administración Intravenosa , Neoplasias de la Corteza Suprarrenal/inmunología , Neoplasias de la Corteza Suprarrenal/mortalidad , Neoplasias de la Corteza Suprarrenal/patología , Carcinoma Corticosuprarrenal/inmunología , Carcinoma Corticosuprarrenal/mortalidad , Carcinoma Corticosuprarrenal/patología , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Progresión de la Enfermedad , Esquema de Medicación , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Supervivencia sin Progresión , Terapia Recuperativa/efectos adversos
15.
Oncol Rep ; 42(2): 866-879, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31233203

RESUMEN

A satisfactory cure rate for renal cell carcinoma (RCC) is difficult to achieve through traditional immunotherapy. RCC has a relatively high spontaneous regression rate due to tumor immune escape. However, tumor­derived exosomes (TEXs), which effectively carry tumor­associated antigens (TAAs) and trigger stronger antigen­specific tumor immunity against autologous tumors than against other tumors, have been widely viewed as attractive potential vaccines for tumor treatment, although improvements are needed. Therefore, in our study, we determined whether RenCa cell­derived exosome (RDE)­stimulated CD8+ T cells exert a stronger specific cytotoxic effect on autologous tumor cells than on other types of tumor cells through the Fas ligand (FasL)/Fas signaling pathway, and whether the combination of RDE­stimulated CD8+ T cells with GM­CSF and IL­12 enhances the anticancer effect. The results showed that RDEs were isolated, as expected, and promoted an increased percentage of CD8+/CD4+ T cells. RDE­stimulated CD8+ T cells also more effectively facilitated cytotoxicity against RenCa cells when combined with GM­CSF and IL­12 in vitro. Furthermore, immunization with RDEs restrained the growth of RenCa tumors in mouse models, and facilitated the stimulation of a stronger specific cytotoxic CD8+ T cell response via the FasL/Fas signaling pathway in vitro. However, these results were observed less frequently for other types of tumor cells after treatment with RDEs, suggesting that RDEs depend on their antigen specificity to trigger antitumor immune responses. These findings revealed that RDE­stimulated CD8+ T cells combined with GM­CSF and IL­12 can more effectively exert a stronger cytotoxic effect than RDEs alone and that RDEs can induce immunization more effectively against renal cortical adenocarcinoma than against other types of cancer. Therefore, according to our study, exosomes are promising potential vaccines, and the combination of exosome­stimulated CD8+ T cells with GM­CSF and IL­12 may be a novel strategy for the treatment of RCC.


Asunto(s)
Carcinoma Corticosuprarrenal/terapia , Linfocitos T CD8-positivos/inmunología , Exosomas/inmunología , Proteína Ligando Fas/metabolismo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/administración & dosificación , Interleucina-12/administración & dosificación , Receptor fas/metabolismo , Neoplasias de la Corteza Suprarrenal/inmunología , Neoplasias de la Corteza Suprarrenal/metabolismo , Carcinoma Corticosuprarrenal/inmunología , Carcinoma Corticosuprarrenal/patología , Animales , Apoptosis , Carcinoma de Células Renales/inmunología , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/terapia , Proliferación Celular , Terapia Combinada , Neoplasias Renales/inmunología , Neoplasias Renales/metabolismo , Ratones , Ratones Endogámicos BALB C , Linfocitos T Citotóxicos/inmunología , Células Tumorales Cultivadas
17.
Curr Oncol Rep ; 21(3): 20, 2019 02 23.
Artículo en Inglés | MEDLINE | ID: mdl-30798468

RESUMEN

PURPOSE OF REVIEW: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy typically with poor prognosis. This review aims to summarize the current knowledge regarding the clinical management of ACC. RECENT FINDINGS: Surgery remains the cornerstone for localized ACC management. In more advanced cases, debulking surgery when feasible can help with hormonal control and may allow the initiation of systemic therapy. Over the last few years, our understanding of ACC molecular pathogenesis has expanded with no significant change in treatment options. Platinum-based chemotherapy is the gold standard in metastatic ACC despite suboptimal efficacy. Tyrosine kinase inhibitor use did not result in meaningful benefit in ACC patients. Multiple clinical trials are currently exploring the role of immunotherapy in ACC. Despite the remarkable improvement in our understanding of the molecular signature and pathways in ACC, this knowledge did not yield a major breakthrough in management of advanced ACC. Multi-institutional and international collaborations are needed to identify promising treatments and new therapeutic targets to improve the care of ACC patients.


Asunto(s)
Neoplasias de la Corteza Suprarrenal/tratamiento farmacológico , Carcinoma Corticosuprarrenal/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Inmunoterapia/métodos , Neoplasias de la Corteza Suprarrenal/inmunología , Neoplasias de la Corteza Suprarrenal/patología , Carcinoma Corticosuprarrenal/inmunología , Carcinoma Corticosuprarrenal/patología , Manejo de la Enfermedad , Humanos , Pronóstico
18.
Pediatr Blood Cancer ; 61(11): 1940-8, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25156210

RESUMEN

BACKGROUND: Low expression of HLA class II antigens has been associated with more aggressive disease in several human malignancies including adult adrenocortical tumors (ACT), but their clinical relevance in pediatric ACT needs to be investigated. PROCEDURE: This study analyzed the expression profile of three class II histocompatibility genes (HLA-DRA, HLA-DPA1, and HLA-DPB1) in 58 consecutive pediatric ACT (13 adenomas and 45 carcinomas) by quantitative real time PCR and their association with clinical and biological features. HLA-DPA1 protein level was determined by immunohistochemistry. RESULTS: A significant association (P < 0.01) was observed between lower expression levels of the three genes analyzed and poor prognostic factors such as age ≥ 4 years, tumor size ≥ 200 cm(3), tumor weight ≥ 100 g, and metastatic disease; the presence of an unfavorable event and death. Underexpression of the HLA-DRA, HLA-DPA1, and HLA-DPB1 genes were associated with lower 5-year event-free survival (EFS) (P = 0.017, P < 0.001, and P = 0.017, respectively). Cox multivariate analysis showed that HLA-DPA1 was an independent prognostic factor (P = 0.029) when analyzed in association with stage IV, age and tumor size. Significantly lower EFS was also observed in patients with negative/weak immunostaining for HLA-DPA1 (P = 0.002). Similar results were observed when only patients classified as having carcinomas were analyzed. CONCLUSION: Our results suggest that lower expression of HLA-DRA, HLA-DPA1, and HLA-DPB1 genes may contribute to more aggressive disease in pediatric ACT. HLA-DPA1 immunostaining may represent potential aggressiveness marker in this tumor.


Asunto(s)
Neoplasias de la Corteza Suprarrenal/inmunología , Cadenas alfa de HLA-DP/genética , Cadenas beta de HLA-DP/genética , Cadenas alfa de HLA-DR/genética , Adolescente , Neoplasias de la Corteza Suprarrenal/mortalidad , Neoplasias de la Corteza Suprarrenal/patología , Niño , Preescolar , Femenino , Cadenas alfa de HLA-DP/análisis , Cadenas beta de HLA-DP/análisis , Cadenas alfa de HLA-DR/análisis , Humanos , Lactante , Masculino , Pronóstico
19.
J Immunol ; 193(5): 2118-26, 2014 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-25063864

RESUMEN

The mechanisms behind destruction of the adrenal glands in autoimmune Addison's disease remain unclear. Autoantibodies against steroid 21-hydroxylase, an intracellular key enzyme of the adrenal cortex, are found in >90% of patients, but these autoantibodies are not thought to mediate the disease. In this article, we demonstrate highly frequent 21-hydroxylase-specific T cells detectable in 20 patients with Addison's disease. Using overlapping 18-aa peptides spanning the full length of 21-hydroxylase, we identified immunodominant CD8(+) and CD4(+) T cell responses in a large proportion of Addison's patients both ex vivo and after in vitro culture of PBLs ≤20 y after diagnosis. In a large proportion of patients, CD8(+) and CD4(+) 21-hydroxylase-specific T cells were very abundant and detectable in ex vivo assays. HLA class I tetramer-guided isolation of 21-hydroxylase-specific CD8(+) T cells showed their ability to lyse 21-hydroxylase-positive target cells, consistent with a potential mechanism for disease pathogenesis. These data indicate that strong CTL responses to 21-hydroxylase often occur in vivo, and that reactive CTLs have substantial proliferative and cytolytic potential. These results have implications for earlier diagnosis of adrenal failure and ultimately a potential target for therapeutic intervention and induction of immunity against adrenal cortex cancer.


Asunto(s)
Enfermedad de Addison/inmunología , Linfocitos T CD8-positivos/inmunología , Proliferación Celular , Inmunidad Celular , Péptidos/inmunología , Esteroide 21-Hidroxilasa/inmunología , Enfermedad de Addison/patología , Adolescente , Neoplasias de la Corteza Suprarrenal/inmunología , Neoplasias de la Corteza Suprarrenal/patología , Adulto , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/patología , Linfocitos T CD8-positivos/patología , Humanos , Persona de Mediana Edad
20.
Hypertension ; 61(2): 526-33, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23248149

RESUMEN

The mechanisms of excess aldosterone secretion in primary aldosteronism (PA) remain poorly understood, although a role for circulating factors has been hypothesized for decades. Agonistic autoantibodies against type-1 angiotensin-II receptor (AT1AA) are detectable in malignant hypertension and preeclampsia and might play a role in PA. Moreover, if they were elevated in aldosterone-producing adenoma (APA) and not in idiopathic hyperaldosteronism (IHA), they might be useful for discriminating between these conditions. To test these hypotheses, we measured the titer of AT1AA in serum of 46 patients with PA (26 with APA, 20 with IHA), 62 with primary hypertension (PH), 13 preeclamptic women, and 45 healthy normotensive blood donors.We found that the AT1AA titer was higher (P<0.05) in both PA and PH patients (2.65 ± 1.55 and 1.86 ± 0.63, respectively) than in normotensive subjects (1.00 ± 0.20). In APA, it was 2-fold higher than in IHA patients (3.43 ± 1.20 versus 1.64 ± 1.39, respectively, P<0.001), despite similar blood pressure values. Of note, it allowed effective discrimination of APA from either PH or IHA, as shown by Receiver Operator Characteristics curve analysis. Moreover, after captopril challenge, plasma aldosterone concentration fell more in AT1AA-positive than in AT1AA-negative PA patients (-32.4% [21.1-42.9] versus 0.0% [0.0-22.6], P=0.015), suggesting an agonistic role for these autoantibodies. Thus, a higher serum AT1AA titer in patients with APA than in IHA and PH patients can be useful in differentiating APA patients from either PH or IHA, and thus in selecting PA patients to be submitted to adrenal vein sampling.


Asunto(s)
Adenoma/metabolismo , Neoplasias de la Corteza Suprarrenal/metabolismo , Aldosterona/metabolismo , Autoanticuerpos/sangre , Hiperaldosteronismo/inmunología , Receptor de Angiotensina Tipo 1/inmunología , Adenoma/diagnóstico , Adenoma/inmunología , Neoplasias de la Corteza Suprarrenal/diagnóstico , Neoplasias de la Corteza Suprarrenal/inmunología , Adulto , Anciano , Aldosterona/sangre , Autoinmunidad/inmunología , Diagnóstico Diferencial , Femenino , Humanos , Hiperaldosteronismo/sangre , Hiperaldosteronismo/diagnóstico , Hipertensión/sangre , Hipertensión/inmunología , Persona de Mediana Edad , Preeclampsia/sangre , Preeclampsia/inmunología , Embarazo
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