title: FOXP3 and CTLA4 overexpression in multiple myeloma bone marrow as a sign of accumulation of CD4(+) T regulatory cells.
abstract: BACKGROUND
  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.
authors.affiliation: Universidade Federal de São Paulo [UNIFESP], Rua Diogo de Faria, 824, 5º andar, Hemocentro, São Paulo, CEP 04037-003, Brazil, wmoises@uol.com.br.
authors.forename: Walter Moises Tobias
authors.initials: WM
authors.lastname: Braga
authors.forename: Bruna Raphaeli
authors.initials: BR
authors.lastname: da Silva
authors.forename: Ana Carolina
authors.initials: AC
authors.lastname: de Carvalho
authors.forename: Yumi H
authors.initials: YH
authors.lastname: Maekawa
authors.forename: Adriana Bruscato
authors.initials: AB
authors.lastname: Bortoluzzo
authors.forename: Edgar Gil
authors.initials: EG
authors.lastname: Rizzatti
authors.forename: Djordje
authors.initials: D
authors.lastname: Atanackovic
authors.forename: Gisele Wally Braga
authors.initials: GW
authors.lastname: Colleoni
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D001853:Bone Marrow / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000166:cytology; D060908:CTLA-4 Antigen / Q000378:metabolism*; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007165:Immunosuppression Therapy; D008297:Male; D008875:Middle Aged; D008998:Monoclonal Gammopathy of Undetermined Significance / Q000235:genetics; D009101:Multiple Myeloma / Q000378:metabolism* / Q000401:mortality; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000378:metabolism; D010954:Plasmacytoma / Q000235:genetics / Q000378:metabolism; D053668:Syndecan-1 / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology*; D058504:Th17 Cells / Q000166:cytology; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D053668:Syndecan-1
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