RESUMEN
The prognosis of patients with relapsed and/or refractory classic Hodgkin lymphoma (cHL) continues to be poor. Therefore, there is a continuing need to develop novel therapies and to rationalize the use of target combinations. In recent years there has been growing interest in epigenetic targets for hematological malignancies under the rationale of the presence of common alterations in epigenetic transcriptional regulation. Since Hodgkin and Reed-Sternberg (HRS) cells have frequent inactivating mutations of the CREBBP and EP300 acetyltransferases, bromodomain and extra-terminal (BET) inhibitors can be a rational therapy for cHL. Here we aimed to confirm the efficacy of BET inhibitors (iBETs) using representative cell models and functional experiments, and to further explore biological mechanisms under iBET treatment using whole-transcriptome analyses. Our results reveal cytostatic rather than cytotoxic activity through the induction of G1/S and G2/M cell-cycle arrest, in addition to variable MYC downregulation. Additionally, massive changes in the transcriptome induced by the treatment include downregulation of relevant pathways in cHL disease: NF-kB and E2F, among others. Our findings support the therapeutic use of iBETs in selected cHL patients and reveal previously unknown biological mechanisms and consequences of pan-BET inhibition.
Asunto(s)
Antineoplásicos , Enfermedad de Hodgkin , Humanos , Células de Reed-Sternberg/metabolismo , Células de Reed-Sternberg/patología , FN-kappa B/metabolismo , Regulación hacia Abajo/genética , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/genética , Enfermedad de Hodgkin/patología , Antineoplásicos/uso terapéuticoRESUMEN
INTRODUCTION: The role of the programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) axis is well established in classical Hodgkin lymphoma (HL), where PD-1 blockade demonstrated spectacular efficacy in relapsed/refractory disease. However, little is known about the frequency and cellular distribution of other immune checkpoints in HL samples. PATIENTS AND METHODS: Using immunohistochemistry, we investigated, along with PD-L1 and PD-1, the expression of lymphocyte-activation gene 3 (LAG-3) and T-cell immunoglobulin and mucin-domain containing 3 (TIM-3) in 57 biopsy samples of patients with classical HL. RESULTS: Hodgkin and Reed/Sternberg (HRS) cells were strongly positive for PD-L1 in nearly all cases. HRS cells were TIM-3 positive in 36% of samples, whereas LAG-3 was rarely expressed (5.2%). In the microenvironment, PD-1, LAG-3, and TIM-3 were expressed by ≥ 5% of cells in 65%, 98%, and 96% of cases, respectively. T-cell rosettes surrounding HRS cells consisted of CD4+ FoxP3- helper T cells expressing both PD-1 and LAG-3, with a variable expression of TIM-3. CONCLUSION: This study demonstrates for the first time that LAG-3 and TIM-3 are nearly always expressed in the microenvironment of classical HL. This may constitute the basis for targeting LAG-3 or TIM-3 in combination with anti-PD-1 antibodies in the treatment of relapsed/refractory HL.
Asunto(s)
Antígenos CD/genética , Regulación Neoplásica de la Expresión Génica , Receptor 2 Celular del Virus de la Hepatitis A/genética , Enfermedad de Hodgkin/genética , Adulto , Anciano , Antígenos CD/análisis , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antígeno B7-H1/análisis , Antígeno B7-H1/genética , Biopsia , Femenino , Receptor 2 Celular del Virus de la Hepatitis A/análisis , Receptor 2 Celular del Virus de la Hepatitis A/antagonistas & inhibidores , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/patología , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Masculino , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/análisis , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/genética , Células de Reed-Sternberg/patología , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Adulto Joven , Proteína del Gen 3 de Activación de LinfocitosRESUMEN
Hodgkin lymphoma (HL) accounts for approximately 0.6% of all new cancer cases, 10% of all lymphomas in the USA, leading to an approximate 9000 new cases per year. It is very unique in that the neoplastic Hodgkin and Reed-Sternberg (HRS) cells of classical HL account for only 1% of the tumor tissue in most cases, with various inflammatory cells including B-cells, T-cells, mast cells, macrophages, eosinophils, neutrophils, and plasma cells comprising the tumor microenvironment. Recent research has identified germinal center B-cells to be the cellular origin of HRS cells. Various transcription factor dysregulation in these neoplastic cells that explains for the loss of B-cell phenotype as well as acquisition of survival and anti-apoptotic features of HRS cells has been identified. Aberrant activation of nuclear factor-kappa B (NF-κB), Janus kinase (JAK)/signal transducer and activator of transcription (STAT), and phosphoinositide 3-kinase (PI3K) pathways play a central role in HL pathogenesis. Both intrinsic genetic mechanisms as well as extrinsic signals have been identified to account for the constitutive activation of these pathways. The extrinsic factors that regulate the activation of transcription pathways in HRS cells have also been studied in detail. Cytokines and chemokines produced both by the HRS cells as well as cells of the microenvironment of HL work in an autocrine and/or paracrine manner to promote survival of HRS cells as well as providing mechanisms for immune escape from the body's antitumor immunity. The understanding of various mechanisms involved in the lymphomagenesis of HL including the importance of its microenvironment has gained much interest in the use of these microenvironmental features as prognostic markers as well as potential treatment targets. In this article, we will review the pathogenesis of HL starting with the cellular origin of neoplastic cells and the mechanisms supporting its pathogenesis, especially focusing on the microenvironment of HL and its associated cytokines.
Asunto(s)
Enfermedad de Hodgkin/etiología , Enfermedad de Hodgkin/patología , Animales , Comunicación Celular , Quimiocinas/metabolismo , Citocinas/metabolismo , Epigénesis Genética , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/virología , Herpesvirus Humano 4/fisiología , Enfermedad de Hodgkin/metabolismo , Humanos , Células de Reed-Sternberg/metabolismo , Células de Reed-Sternberg/patología , Transducción de Señal , Microambiente TumoralRESUMEN
PURPOSE: The purpose of the present study was to examine the relationship between the serum levels of soluble CD 30 (S-sCD 30), the Hodgkin and Reed Sternberg (HRS) cell density and the macroscopic tumour burden in untreated patients with Hodgkin's disease (HD). MATERIALS AND METHODS: In 126 untreated patients with HD diagnosed between 1979-1991, (79 males and 47 females, median age 33 years) S-sCD 30 was measured using frozen serum samples. The number of HRS cells (the HRS cell density) was counted in 10 high-power vision fields. The macroscopic tumour volume was estimated in 70 patients in stages I and II by counting the number of involved sites and scoring them according to size. RESULTS: Soluble CD 30 was detected in the sera of all patients. The levels were significantly higher in patients with high HRS cell density, high macroscopic tumour burden, stages III-IV, B symptoms and bulky disease. Patients with high S-sCD 30 had a significantly poorer DFS (p < 0.05) and survival (p < 0.001). High HRS cell density correlated to large macroscopic tumour burden, stage IV disease and B-symptoms. Patients with the highest HRS cell density had a significantly poorer disease-free survival (DFS) (p < 0.01) and survival (p < 0.01). In a multivariate analysis, S-sCD 30 was more important as regards prognosis than HRS cell density. CONCLUSIONS: Serum levels of sCD 30 are probably a measurement of tumour burden in HD and are also strongly related to the prognosis. A high number of HRS cells correlated to an extensive spread HD and also to prognosis.