title: BRAF V600E in papillary thyroid carcinoma is associated with increased programmed death ligand 1 expression and suppressive immune cell infiltration.
abstract: BACKGROUND
  There remain a small number of patients with papillary thyroid cancer (PTC) who suffer recurrence, metastases, or death. While mutation of the BRAF gene, corresponding to the constitutively active BRAF(V600E) protein, has been associated with worse clinical outcomes in thyroid cancer, the reasons underlying this observation are presently unknown. Disruption of endogenous host immune surveillance and promotion of tumor immune escape is one mechanism by which BRAF(V600E) tumors may achieve more aggressive behavior. This study evaluated the relationship between BRAF(V600E) status and known strategies of tumor-mediated immune suppression.
  
  
  METHODS
  Tissue sections of PTC tumors from 33 patients were evaluated by immunohistochemistry for tumor-expressed suppressive ligands and enzymes and effector and suppressor populations of tumor-infiltrating immune cells. Presence of BRAF(V600E) was evaluated by direct DNA sequencing of PTC specimens and the results correlated with tumor-expressed molecules and tumor-infiltrating immune cell populations, as well as patient characteristics and pathologic findings.
  
  
  RESULTS
  BRAF(V600E) tumors more often express high levels of immunosuppressive ligands programmed death ligand 1 (53% vs. 12.5%) and human leukocyte antigen G (41% vs. 12.5%) compared to BRAF wild-type tumors. There was no association between indoleamine 2,3-dioxygenase 1 expression and BRAF(V600E) status. Furthermore, BRAF(V600E) tumors demonstrate both lower CD8(+) effector to FoxP3(+) regulatory T cell, and CD68(+) pan-macrophage to CD163(+) M2 macrophage ratios, indicating relative increases in suppressive T cell and macrophage components, respectively.
  
  
  CONCLUSIONS
  Overall, BRAF(V600E) PTC tumors display a broadly immunosuppressive profile and evidence of disturbed host tumor immune surveillance that may contribute to the poorer outcomes observed in this subset of patients with thyroid cancer.
authors: 1 Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital and the Harvard Medical School , Boston, Massachusetts.
authors: Trevor E
authors: TE
authors: Angell
authors: Melissa G
authors: MG
authors: Lechner
authors: Julie K
authors: JK
authors: Jang
authors: Adrian J
authors: AJ
authors: Correa
authors: Jonathan S
authors: JS
authors: LoPresti
authors: Alan L
authors: AL
authors: Epstein
mesh_terms: D000328:Adult; D000368:Aged; D060890:B7-H1 Antigen / Q000378:metabolism*; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D059951:HLA-G Antigens / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D055815:Young Adult
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; D059951:HLA-G Antigens; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf