Histopathologic and immunophenotypical characterization of diffuse large B cell lymphoma of the elderly and correlation with microRNAs expression profile

• Grant number: 14/23093-7
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: January 01, 2015
• End date: June 30, 2017
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Gisele Wally Braga Colleoni
• Grantee: Wagner Augusto Poles
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated research grant: 10/17668-6 - Identification of biomarkers and possible therapeutical targets in B-cell lymphoproliferative disorders, AP.TEM

Abstract

The World Health Organization (WHO) classification of tumors of hematopoietic and lymphoid tissue has recently recognized a new entity, designated EBV (Epstein-Barr virus) -positive Diffuse Large B Cell Lymphoma of the elderly (EBV+DLBCLe). Although the exact trigger mechanism for this entity is not fully understood, it has been postulated that EBV+DLBCLe might be caused by the senescence of the immune system as a part of normal aging. These lesions may include impaired effector B and T cells response, in addition to loss of naïve T cell diversity. Epstein-Barr virus intrinsic mechanisms may also play an important role on this entity pathogenesis by expression of specific sets of viral proteins, interaction with host molecules and epigenetic gene regulation, including microRNA-mediated mechanisms. In particular, hsa-miR-155, within the context of EBV+DLBCLe morphologic variants, is of particular importance due to its ability to interfere with functionality and differentiation pattern of tumor-microenvironment associated cells. Within the tumor, myeloid cells accumulate mostly in the form of tumor-associated macrophages (TAMs). TAMs are heterogeneous, with some subsets likely acting as antigen presenting cells (APCs), eliciting antitumor immunity (M1 phenotype). Moreover, another TAM subset (M2 phenotype) fulfill tissue-remodeling function thus favoring tumor growth and progression by supporting angiogenesis, invasions and metastasis. Has-mir-155 is required to induce TAMs M1 phenotype, thus activating a proinflammatory state in this subset, in addition to its antigen-presenting function and therefore promoting an antitumor immune response, especially during the early stages of carcinogenesis. Recent reports suggest an increase in tumor growth associated with has-miR-155 insufficiency in myeloid cells, particularly, in APCs such as macrophages and dendritic cells due to decrease in inflammatory response. Hence, this study aims to: 1) characterize morphology and immunohistochemical phenotype of Andrade et al (2013) EBV+DLBCLe cases assessed in the pilot and multicenter study; (2) characterize EBV+DLBCLe tumor-associated macrophages polarization pattern; (3) evaluate hsa-miR-155 expression, extracted from EBV+DLBCLe cases and compare it to EBV-DLBCLe, in order to validate previous data obtained from Andrade et al study. (AU)