title: Vemurafenib reverses immunosuppression by myeloid derived suppressor cells.
abstract: Myeloid derived suppressor cells (MDSCs) suppress innate and adaptive immunity, thereby limiting anti-tumor immune responses in cancer patients. In patients with advanced melanoma, the phenotype and function of MDSCs remains controversial. In our study, we further explored two distinct subpopulations of MDSCs and investigated the impact of Vemurafenib on these cells. Flow cytometry analysis revealed that in comparison to healthy donors and patients with localized disease, PBMCs from patients with metastatic melanoma showed an increased frequency of CD14(+) HLA-DR(-/low) monocytic MDSCs (moMDSCs) and of a previously unrecognized population of CD14(-) CD66b(+) Arginase1(+) granulocytic MDSCs (grMDSCs). In vitro, both populations suppressed autologous T-cell proliferation, which was tested in CFSE-based proliferation assays. Vemurafenib treatment of melanoma patients reduced the frequency of both moMDSCs and grMDSCs. According to our in vivo finding, conditioned medium (CM) from Vemurafenib treated melanoma cells was less active in inducing moMDSCs in vitro than CM from untreated melanoma cells. In conclusion, patients with advanced melanoma show increased levels of moMDSCs, and of a population of CD14(-) CD66b(+) Arginase1(+) grMDSCs. Both MDSCs are distinct populations capable of suppressing autologous T-cell responses independently of each other. In vitro as well as in vivo, Vemurafenib inhibits the generation of human moMDSCs. Thus, Vemurafenib decreases immunosuppression in patients with advanced melanoma, indicating its potential as part of future immunotherapies.
authors.affiliation: Department of Dermatology, University Hospital, University Duisburg-Essen, Essen, Germany. bastian.schilling@uk-essen.de
authors.forename: Bastian
authors.initials: B
authors.lastname: Schilling
authors.forename: Antje
authors.initials: A
authors.lastname: Sucker
authors.forename: Klaus
authors.initials: K
authors.lastname: Griewank
authors.forename: Fang
authors.initials: F
authors.lastname: Zhao
authors.forename: Benjamin
authors.initials: B
authors.lastname: Weide
authors.forename: André
authors.initials: A
authors.lastname: Görgens
authors.forename: Bernd
authors.initials: B
authors.lastname: Giebel
authors.forename: Dirk
authors.initials: D
authors.lastname: Schadendorf
authors.forename: Annette
authors.initials: A
authors.lastname: Paschen
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000378:metabolism; D001119:Arginase / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005260:Female; D058851:GPI-Linked Proteins / Q000378:metabolism; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects*; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000276:immunology*; D008875:Middle Aged; D022423:Myeloid Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000276:immunology; D014407:Tumor Cells, Cultured; D000077484:Vemurafenib
chemical_list: D015703:Antigens, CD; C504120:CEACAM8 protein, human; D015815:Cell Adhesion Molecules; D017077:Culture Media, Conditioned; D058851:GPI-Linked Proteins; D006684:HLA-DR Antigens; D007211:Indoles; D018950:Lipopolysaccharide Receptors; D013449:Sulfonamides; D000077484:Vemurafenib; C574619:ARG1 protein, human; D001119:Arginase
keywords: MDSC; melanoma; vemurafenib