title: Selective BRAF inhibitors induce marked T-cell infiltration into human metastatic melanoma.
abstract: OBJECTIVE
  To evaluate the effects of treatment with the potent mutant BRAF inhibitors GSK2118436 or vemurafenib (PLX4720) on immune responses to metastatic melanoma in tissues taken before and after treatment.
  
  
  METHODS
  Thirty-seven tumor biopsies were collected from 15 patients with unresectable American Joint Committee on Cancer stage III or IV melanoma immediately before and approximately 7 days after the commencement of BRAF inhibitor treatment and at the time of tumor progression. Immunohistochemical staining was carried out on the biopsies using specific antibodies for CD8, CD4, CD20, CD1a, and Granzyme B.
  
  
  RESULTS
  Tumor infiltration by CD4(+) and CD8(+) lymphocytes increased markedly following BRAF inhibitor treatment (both ρ = 0.015). There was a correlation between the degree of tumor infiltration by CD8(+) and Granzyme B-expressing lymphocytes in post-BRAF inhibitor-treated biopsies (r = 0.690 and ρ = 0.013). Increased intratumoral CD8(+) lymphocyte expression was correlated with a reduction in tumor size and an increase in necrosis in posttreatment biopsies (r = -0.793, ρ = 0.011; and r = 0.761, ρ = 0.004, respectively).
  
  
  CONCLUSIONS
  The increase in tumor-infiltrating lymphocytes induced by treatment with BRAF inhibitors provides strong support for conducting trials that combine BRAF inhibitors with immunotherapy in the hope of prolonging clinical responses.
authors.affiliation: Melanoma Institute Australia, Sydney, NSW, Australia. james.wilmott@smu.org.au
authors.forename: James S
authors.initials: JS
authors.lastname: Wilmott
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Long
authors.forename: Julie R
authors.initials: JR
authors.lastname: Howle
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Haydu
authors.forename: Raghwa N
authors.initials: RN
authors.lastname: Sharma
authors.forename: John F
authors.initials: JF
authors.lastname: Thompson
authors.forename: Richard F
authors.initials: RF
authors.lastname: Kefford
authors.forename: Peter
authors.initials: P
authors.lastname: Hersey
authors.forename: Richard A
authors.initials: RA
authors.lastname: Scolyer
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D053804:Granzymes / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects* / Q000276:immunology; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology*; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D010091:Oximes / Q000494:pharmacology / Q000627:therapeutic use; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D055815:Young Adult
chemical_list: D007093:Imidazoles; D007211:Indoles; D010091:Oximes; C528407:PLX 4720; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D048493:Proto-Oncogene Proteins B-raf; D053804:Granzymes; C561627:dabrafenib