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

Walter Moises Tobias Braga,Bruna Raphaeli Da Silva,Yumi H Maekawa,Djordje Atanackovic,Adriana Bruscato Bortoluzzo,Ana Carolina De Carvalho,Edgar Gil Rizzatti,Gisele Wally Braga Colleoni

doi:10.1007/s00262-014-1589-9

Abstract

IntroductionMultiple 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.MethodsExpression 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.ConclusionsOverexpression 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00262-014-1589-9) contains supplementary material, which is available to authorized users.

Highlights

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
We analyzed BM expression of other genes related to T regulatory (Treg) and Th17 cell subpopulations
We observed the overexpression of FOXP3 and CTLA4 in the BM of myeloma patients when compared to healthy controls

Summary

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. CD4+ T cells are induced by IL-10 and secrete both IL-10 and transforming growth factor β (TGFβ) converting peripheral naïve CD4+ CD25− FOXP3− cells to FOXP3-expressing cells. Regardless of their origin, they share one key feature: their ability to potently suppress effector T cells (Teff). This suppressive activity of Treg cells is associated with the overexpression of FOXP3, a member of the forkhead/winged helix family, which acts as a transcriptional repressor [3], and CTLA4, a coinhibitory molecule that maintains immune homeostasis by down regulating T cell-related costimulatory pathways. FOXP3-expressing cells in cancer settings have been correlated with poor anti-tumor effector response, compromising tumor immunity [4, 5]

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