title: Oncogenic BRAF(V600E) promotes stromal cell-mediated immunosuppression via induction of interleukin-1 in melanoma.
abstract: OBJECTIVE
  In this study, we assessed the specific role of BRAF(V600E) signaling in modulating the expression of immune regulatory genes in melanoma, in addition to analyzing downstream induction of immune suppression by primary human melanoma tumor-associated fibroblasts (TAF).
  
  
  METHODS
  Primary human melanocytes and melanoma cell lines were transduced to express WT or V600E forms of BRAF, followed by gene expression analysis. The BRAF(V600E) inhibitor vemurafenib was used to confirm targets in BRAF(V600E)-positive melanoma cell lines and in tumors from melanoma patients undergoing inhibitor treatment. TAF lines generated from melanoma patient biopsies were tested for their ability to inhibit the function of tumor antigen-specific T cells, before and following treatment with BRAF(V600E)-upregulated immune modulators. Transcriptional analysis of treated TAFs was conducted to identify potential mediators of T-cell suppression.
  
  
  RESULTS
  Expression of BRAF(V600E) induced transcription of interleukin 1 alpha (IL-1α) and IL-1β in melanocytes and melanoma cell lines. Further, vemurafenib reduced the expression of IL-1 protein in melanoma cell lines and most notably in human tumor biopsies from 11 of 12 melanoma patients undergoing inhibitor treatment. Treatment of melanoma-patient-derived TAFs with IL-1α/β significantly enhanced their ability to suppress the proliferation and function of melanoma-specific cytotoxic T cells, and this inhibition was partially attributable to upregulation by IL-1 of COX-2 and the PD-1 ligands PD-L1 and PD-L2 in TAFs.
  
  
  CONCLUSIONS
  This study reveals a novel mechanism of immune suppression sensitive to BRAF(V600E) inhibition, and indicates that clinical blockade of IL-1 may benefit patients with BRAF wild-type tumors and potentially synergize with immunotherapeutic interventions.
authors: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Jahan S
authors: JS
authors: Khalili
authors: Shujuan
authors: S
authors: Liu
authors: Tania G
authors: TG
authors: Rodríguez-Cruz
authors: Mayra
authors: M
authors: Whittington
authors: Seth
authors: S
authors: Wardell
authors: Chengwen
authors: C
authors: Liu
authors: Minying
authors: M
authors: Zhang
authors: Zachary A
authors: ZA
authors: Cooper
authors: Dennie T
authors: DT
authors: Frederick
authors: Yufeng
authors: Y
authors: Li
authors: Min
authors: M
authors: Zhang
authors: Richard W
authors: RW
authors: Joseph
authors: Chantale
authors: C
authors: Bernatchez
authors: Suhendan
authors: S
authors: Ekmekcioglu
authors: Elizabeth
authors: E
authors: Grimm
authors: Laszlo G
authors: LG
authors: Radvanyi
authors: Richard E
authors: RE
authors: Davis
authors: Michael A
authors: MA
authors: Davies
authors: Jennifer A
authors: JA
authors: Wargo
authors: Patrick
authors: P
authors: Hwu
authors: Gregory
authors: G
authors: Lizée
mesh_terms: D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007165:Immunosuppression Therapy; D007211:Indoles / Q000008:administration & dosage; D053582:Interleukin-1alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008544:Melanocytes / Q000166:cytology / Q000187:drug effects; D008545:Melanoma / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000276:immunology; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects; D013449:Sulfonamides / Q000008:administration & dosage; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D059016:Tumor Microenvironment / Q000276:immunology; D000077484:Vemurafenib
chemical_list: D000951:Antigens, Neoplasm; D007211:Indoles; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf