title: BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma.
abstract: OBJECTIVE
  To evaluate the effects of BRAF inhibition on the tumor microenvironment in patients with metastatic melanoma.
  
  
  METHODS
  Thirty-five biopsies were collected from 16 patients with metastatic melanoma pretreatment (day 0) and at 10 to 14 days after initiation of treatment with either BRAF inhibitor alone (vemurafenib) or BRAF + MEK inhibition (dabrafenib + trametinib) and were also taken at time of progression. Biopsies were analyzed for melanoma antigens, T-cell markers, and immunomodulatory cytokines.
  
  
  RESULTS
  Treatment with either BRAF inhibitor alone or BRAF + MEK inhibitor was associated with an increased expression of melanoma antigens and an increase in CD8+ T-cell infiltrate. This was also associated with a decrease in immunosuppressive cytokines [interleukin (IL)-6 and IL-8] and an increase in markers of T-cell cytotoxicity. Interestingly, expression of exhaustion markers TIM-3 and PD1 and the immunosuppressive ligand PDL1 was increased on treatment. A decrease in melanoma antigen expression and CD8 T-cell infiltrate was noted at time of progression on BRAF inhibitor alone and was reversed with combined BRAF and MEK inhibition.
  
  
  CONCLUSIONS
  Together, these data suggest that treatment with BRAF inhibition enhances melanoma antigen expression and facilitates T-cell cytotoxicity and a more favorable tumor microenvironment, providing support for potential synergy of BRAF-targeted therapy and immunotherapy. Interestingly, markers of T-cell exhaustion and the immunosuppressive ligand PDL1 are also increased with BRAF inhibition, further implying that immune checkpoint blockade may be critical in augmenting responses to BRAF-targeted therapy in patients with melanoma.
authors: Division of Surgical Oncology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors: Dennie T
authors: DT
authors: Frederick
authors: Adriano
authors: A
authors: Piris
authors: Alexandria P
authors: AP
authors: Cogdill
authors: Zachary A
authors: ZA
authors: Cooper
authors: Cecilia
authors: C
authors: Lezcano
authors: Cristina R
authors: CR
authors: Ferrone
authors: Devarati
authors: D
authors: Mitra
authors: Andrea
authors: A
authors: Boni
authors: Lindsay P
authors: LP
authors: Newton
authors: Chengwen
authors: C
authors: Liu
authors: Weiyi
authors: W
authors: Peng
authors: Ryan J
authors: RJ
authors: Sullivan
authors: Donald P
authors: DP
authors: Lawrence
authors: F Stephen
authors: FS
authors: Hodi
authors: Willem W
authors: WW
authors: Overwijk
authors: Gregory
authors: G
authors: Lizée
authors: George F
authors: GF
authors: Murphy
authors: Patrick
authors: P
authors: Hwu
authors: Keith T
authors: KT
authors: Flaherty
authors: David E
authors: DE
authors: Fisher
authors: Jennifer A
authors: JA
authors: Wargo
mesh_terms: D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005455:Fluorescent Antibody Technique; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008545:Melanoma / Q000276:immunology / Q000378:metabolism* / Q000556:secondary; D058950:Melanoma-Specific Antigens / Q000378:metabolism*; D009367:Neoplasm Staging; D010091:Oximes / Q000494:pharmacology*; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology*; D059016:Tumor Microenvironment; D000077484:Vemurafenib
chemical_list: D014408:Biomarkers, Tumor; D007093:Imidazoles; D007211:Indoles; D058950:Melanoma-Specific Antigens; D010091:Oximes; D011728:Pyridones; D011744:Pyrimidinones; D012333:RNA, Messenger; D013449:Sulfonamides; D000077484:Vemurafenib; C560077:trametinib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048369:MAP Kinase Kinase 1; C561627:dabrafenib