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Open Access 01-11-2014 | Original Article

FOXP3 and CTLA4 overexpression in multiple myeloma bone marrow as a sign of accumulation of CD4⁺ T regulatory cells

Authors: Walter Moises Tobias Braga, Bruna Raphaeli da Silva, Ana Carolina de Carvalho, Yumi H. Maekawa, Adriana Bruscato Bortoluzzo, Edgar Gil Rizzatti, Djordje Atanackovic, Gisele Wally Braga Colleoni

Published in: Cancer Immunology, Immunotherapy | Issue 11/2014

Abstract

Introduction

Multiple myeloma (MM) development involves a series of genetic abnormalities and changes in the bone marrow (BM) microenvironment, favoring the growth of the tumor and failure of local immune control. T regulatory (Treg) cells play an important role in dampening anti-tumor immune responses while T-helper-17 (Th17) cells seem to be critical for the eradication of malignant cells. The aim of our study was to characterize the expression of Treg- and Th17-related genes in total myeloma BM samples to assess their role as biomarkers, prognostic factors, and possible therapeutic targets in this incurable disease.

Methods

Expression of markers for Treg (FOXP3, CTLA4) and Th17 cells (RORγt) was determined by quantitative real-time PCR in BM aspirates of 46 MM patients, four patients with monoclonal gammopathy of undetermined significance, five solitary plasmacytomas, and five healthy BM donors. Gene expression was evaluated regarding an influence on the patients’ overall survival (OS).

Results

FOXP3 and CTLA4 presented a sixfold (p = 0.02) and 30-fold higher expression (p = 0.03), respectively, in MM patients than in controls. RORγt expression was similar in MM patients and controls. Median OS of MM patients was 16.8 (range 4.5–29.1) months, and international staging system was the only independent prognostic factor for patients survival.

Conclusions

Overexpression of FOXP3 and CTLA4 in total BM samples suggests a local accumulation of immunosuppressive Tregs, the MM tumor environment, possibly dampening anti-tumor host immune responses. Therapeutic approaches targeting Treg cells and restoring local anti-tumor immunity may provide new treatment strategies for this incurable malignancy.

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Title: FOXP3 and CTLA4 overexpression in multiple myeloma bone marrow as a sign of accumulation of CD4+ T regulatory cells
Authors: Walter Moises Tobias Braga
Bruna Raphaeli da Silva
Ana Carolina de Carvalho
Yumi H. Maekawa
Adriana Bruscato Bortoluzzo
Edgar Gil Rizzatti
Djordje Atanackovic
Gisele Wally Braga Colleoni
Publication date: 01-11-2014
Publisher: Springer Berlin Heidelberg
Published in: Cancer Immunology, Immunotherapy / Issue 11/2014
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-014-1589-9

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