title: Effects of MAPK and PI3K pathways on PD-L1 expression in melanoma.
abstract: OBJECTIVE
  PD-L1 is the main ligand for the immune inhibitory receptor PD-1. This ligand is frequently expressed by melanoma cells. In this study, we investigated whether PD-L1 expression is controlled by melanoma driver mutations and modified by oncogenic signaling inhibition.
  
  
  METHODS
  Expression of PD-L1 was investigated in a panel of 51 melanoma cell lines containing different oncogenic mutations, including cell lines with innate and acquired resistance to BRAF inhibitors (BRAFi). The effects of targeted therapy drugs on expression of PD-L1 by melanoma cells were investigated.
  
  
  RESULTS
  No association was found between the level of PD-L1 expression and mutations in BRAF, NRAS, PTEN, or amplification of AKT. Resistance to vemurafenib due to the activation of alternative signaling pathways was accompanied with the induction of PD-L1 expression, whereas the resistance due to the reactivation of the MAPK pathway had no effect on PD-L1 expression. In melanoma cell lines, the effects of BRAF, MEK, and PI3K inhibitors on expression of PD-L1 were variable from reduction to induction, particularly in the presence of INFγ. In PD-L1-exposed lymphocytes, vemurafenib paradoxically restored activity of the MAPK pathway and increased the secretion of cytokines.
  
  
  CONCLUSIONS
  In melanoma cell lines, including BRAFi-resistant cells, PD-L1 expression is variably regulated by oncogenic signaling pathways. PD-L1-exposed lymphocytes decrease MAPK signaling, which is corrected by exposure to vemurafenib, providing potential benefits of combining this drug with immunotherapies.
authors.affiliation: Authors' Affiliations: Division of Hematology-Oncology, Department of Medicine;
authors.forename: Mohammad
authors.initials: M
authors.lastname: Atefi
authors.affiliation: Authors' Affiliations: Division of Hematology-Oncology, Department of Medicine;
authors.forename: Earl
authors.initials: E
authors.lastname: Avramis
authors.affiliation: Authors' Affiliations: Division of Hematology-Oncology, Department of Medicine;
authors.forename: Amanda
authors.initials: A
authors.lastname: Lassen
authors.affiliation: Authors' Affiliations: Division of Hematology-Oncology, Department of Medicine;
authors.forename: Deborah J L
authors.initials: DJ
authors.lastname: Wong
authors.affiliation: Authors' Affiliations: Division of Hematology-Oncology, Department of Medicine;
authors.forename: Lidia
authors.initials: L
authors.lastname: Robert
authors.affiliation: Authors' Affiliations: Division of Hematology-Oncology, Department of Medicine;
authors.forename: David
authors.initials: D
authors.lastname: Foulad
authors.affiliation: Authors' Affiliations: Division of Hematology-Oncology, Department of Medicine;
authors.forename: Michael
authors.initials: M
authors.lastname: Cerniglia
authors.affiliation: Authors' Affiliations: Division of Hematology-Oncology, Department of Medicine;
authors.forename: Bjoern
authors.initials: B
authors.lastname: Titz
authors.affiliation: Authors' Affiliations: Division of Hematology-Oncology, Department of Medicine;
authors.forename: Thinle
authors.initials: T
authors.lastname: Chodon
authors.affiliation: Department of Molecular and Medical Pharmacology; and Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, California.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Graeber
authors.affiliation: Division of Surgical-Oncology, Department of Surgery; Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, California.
authors.forename: Begonya
authors.initials: B
authors.lastname: Comin-Anduix
authors.affiliation: Authors' Affiliations: Division of Hematology-Oncology, Department of Medicine; Division of Surgical-Oncology, Department of Surgery; Department of Molecular and Medical Pharmacology; and Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, California aribas@mednet.ucla.edu.
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
mesh_terms: D060890:B7-H1 Antigen / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D008545:Melanoma / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D000077484:Vemurafenib
chemical_list: D060890:B7-H1 Antigen; D016207:Cytokines; D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib; D019869:Phosphatidylinositol 3-Kinases; D048493:Proto-Oncogene Proteins B-raf; D020928:Mitogen-Activated Protein Kinases