title: Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function.
abstract: Targeted therapy against the BRAF/mitogen-activated protein kinase (MAPK) pathway is a promising new therapeutic approach for the treatment of melanoma. Treatment with selective BRAF inhibitors results in a high initial response rate but limited duration of response. To counter this, investigators propose combining this therapy with other targeted agents, addressing the issue of redundancy and signaling through different oncogenic pathways. An alternative approach is combining BRAF/MAPK-targeted agents with immunotherapy. Preliminary evidence suggests that oncogenic BRAF (BRAF(V600E)) contributes to immune escape and that blocking its activity via MAPK pathway inhibition leads to increased expression of melanocyte differentiation antigens (MDA). Recognition of MDAs is a critical component of the immunologic response to melanoma, and several forms of immunotherapy capitalize on this recognition. Among the various approaches to inhibiting BRAF/MAPK, broad MAPK pathway inhibition may have deleterious effects on T lymphocyte function. Here, we corroborate the role of oncogenic BRAF in immune evasion by melanoma cells through suppression of MDAs. We show that inhibition of the MAPK pathway with MAPK/extracellular signal-regulated kinase kinase (MEK) inhibitors or a specific inhibitor of BRAF(V600E) in melanoma cell lines and tumor digests results in increased levels of MDAs, which is associated with improved recognition by antigen-specific T lymphocytes. However, treatment with MEK inhibitors impairs T lymphocyte function, whereas T-cell function is preserved after treatment with a specific inhibitor of BRAF(V600E). These findings suggest that immune evasion of melanomas mediated by oncogenic BRAF may be reversed by targeted BRAF inhibition without compromising T-cell function. These findings have important implications for combined kinase-targeted therapy plus immunotherapy for melanoma.
authors.affiliation: Division of Surgical Oncology, Medical Oncology, and Dermatology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Boni
authors.forename: Alexandria P
authors.initials: AP
authors.lastname: Cogdill
authors.forename: Ping
authors.initials: P
authors.lastname: Dang
authors.forename: Durga
authors.initials: D
authors.lastname: Udayakumar
authors.forename: Ching-Ni Jenny
authors.initials: CN
authors.lastname: Njauw
authors.forename: Callum M
authors.initials: CM
authors.lastname: Sloss
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Ferrone
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty
authors.forename: Donald P
authors.initials: DP
authors.lastname: Lawrence
authors.forename: David E
authors.initials: DE
authors.lastname: Fisher
authors.forename: Hensin
authors.initials: H
authors.lastname: Tsao
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Wargo
mesh_terms: D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D001549:Benzamides / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D058965:MART-1 Antigen; D008545:Melanoma / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology* / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D009570:Nitriles / Q000494:pharmacology; D010088:Oxidoreductases / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology*; D058951:gp100 Melanoma Antigen
chemical_list: D000951:Antigens, Neoplasm; D001549:Benzamides; D002070:Butadienes; D018984:Epitopes, T-Lymphocyte; D058965:MART-1 Antigen; C548667:MLANA protein, human; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D009570:Nitriles; C548637:PMEL protein, human; C113580:U 0126; D058951:gp100 Melanoma Antigen; C506614:mirdametinib; D004159:Diphenylamine; D010088:Oxidoreductases; C489799:TYRP1 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase