title: PD-L1 Expression and Tumor-Infiltrating Lymphocytes Define Different Subsets of MAPK Inhibitor-Treated Melanoma Patients.
abstract: OBJECTIVE
  To evaluate the expression of tumor PD-L1 and changes in tumor-infiltrating lymphocyte (TIL) populations in patients with metastatic melanoma treated with targeted MAPK inhibitors.
  
  
  METHODS
  Ninety-three tumors were analyzed from 40 patients treated with a BRAF inhibitor alone (BRAFi; n = 28) or combination of BRAF and MEK inhibitors (Combi; n = 12). Tumors were excised before treatment (PRE), early during treatment (EDT), and at progression (PROG). Immunohistochemical staining was performed for CD4, CD8, CD68, FOXP3, LAG3, PD-1, and PD-L1 and correlated with clinical outcome.
  
  
  RESULTS
  Patients' tumors that were PD-L1 positive at baseline showed a significant decrease in PD-L1 expression at PROG (P = 0.028), whereas patients' tumors that were PD-L1 negative at baseline showed a significant increase in PD-L1 expression at PROG (P = 0.008) irrespective of treatment with BRAFi or Combi. Overall PD-L1 expression highly correlated with TIL immune markers. BRAFi-treated patients showed significant increases in CD4(+), CD8(+), and PD-1(+) lymphocytes from PRE to EDT (P = 0.001, P = 0.001, P = 0.017, respectively), and Combi-treated patients showed similar increases in CD4(+) and CD8(+) lymphocytes from PRE to EDT (P = 0.017, P = 0.021).
  
  
  CONCLUSIONS
  The addition of MEKi to BRAFi did not result in significant reduction in immune infiltration in EDT biopsies. This provides support for conducting trials that combine MAPKi with immune checkpoint inhibitors in the hope of improving complete and durable response rates. PD-L1 expression at PROG on MAPK inhibitors varied according to baseline expression suggesting that combining MAPKi with immunotherapies concurrently may be more effective in patients with PD-L1 expression and TILs in baseline melanoma samples.
authors.affiliation: Melanoma Institute Australia, North Sydney, New South Wales, Australia. Sydney Medical School, the University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Hojabr
authors.initials: H
authors.lastname: Kakavand
authors.affiliation: Melanoma Institute Australia, North Sydney, New South Wales, Australia. Sydney Medical School, the University of Sydney, Sydney, New South Wales, Australia.
authors.forename: James S
authors.initials: JS
authors.lastname: Wilmott
authors.affiliation: Melanoma Institute Australia, North Sydney, New South Wales, Australia. Sydney Medical School, the University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Menzies
authors.affiliation: Melanoma Institute Australia, North Sydney, New South Wales, Australia. Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Vilain
authors.affiliation: Melanoma Institute Australia, North Sydney, New South Wales, Australia. Sydney Medical School, the University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Haydu
authors.affiliation: Merck Research Laboratories, Palo Alto, California.
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Yearley
authors.affiliation: Melanoma Institute Australia, North Sydney, New South Wales, Australia. Sydney Medical School, the University of Sydney, Sydney, New South Wales, Australia.
authors.forename: John F
authors.initials: JF
authors.lastname: Thompson
authors.affiliation: Melanoma Institute Australia, North Sydney, New South Wales, Australia. Crown Princess Mary Cancer Centre, Westmead Hospital, New South Wales, Australia. Australian School of Advanced Medicine, Macquarie University, New South Wales, Australia.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Kefford
authors.affiliation: Melanoma Institute Australia, North Sydney, New South Wales, Australia. Sydney Medical School, the University of Sydney, Sydney, New South Wales, Australia. Kolling Institute of Medical Research, Royal North Shore Hospital, St. Leonards, New South Wales, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Hersey
authors.affiliation: Melanoma Institute Australia, North Sydney, New South Wales, Australia. Sydney Medical School, the University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Long
authors.affiliation: Melanoma Institute Australia, North Sydney, New South Wales, Australia. Sydney Medical School, the University of Sydney, Sydney, New South Wales, Australia. Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia. richard.scolyer@sswahs.nsw.gov.au.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Scolyer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D060890:B7-H1 Antigen / Q000378:metabolism*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use; D007150:Immunohistochemistry; D007211:Indoles / Q000627:therapeutic use; D053208:Kaplan-Meier Estimate; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology*; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D008875:Middle Aged; D010091:Oximes / Q000627:therapeutic use; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors; D011728:Pyridones / Q000627:therapeutic use; D011744:Pyrimidinones / Q000627:therapeutic use; D013449:Sulfonamides / Q000627:therapeutic use; D000077484:Vemurafenib; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D007093:Imidazoles; D007211:Indoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; D013449:Sulfonamides; D000077484:Vemurafenib; C560077:trametinib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020930:MAP Kinase Kinase Kinases; C561627:dabrafenib