title: BRAF inhibition improves tumor recognition by the immune system: Potential implications for combinatorial therapies against melanoma involving adoptive T-cell transfer.
abstract: In spite of the fact that they occur at high rates, the clinical responses of BRAF(V600) mutant metastatic melanoma to BRAF inhibitors are usually short-lasting, with most cases progressing within less than 8 mo. Immunomodulatory strategies initiated after progression have recently been reported to be poorly efficient. By characterizing the immunological interactions between T cells and cancer cells in clinical material as well as the influence of the FDA-approved BRAF inhibitor vemurafenib on the immune system, we aimed at unraveling new strategies to expand the efficacy of adoptive T-cell transfer, which represents one of the most promising approaches currently in clinical development for the treatment of metastatic melanoma. Here we show that blocking the BRAF-MAPK pathway in BRAF signaling-addicted melanoma cells significantly increases the ability of T cells contained in clinical grade tumor-infiltrating lymphocytes to recognize autologous BRAF(V600) mutant melanoma cell lines in vitro. Antitumor reactivity was improved regardless of the class of antigen recognized by tumor-specific CD8(+) T cells. Microarray data suggests that improved tumor recognition is associated with modified expression of MHC Class I-associated proteins as well as of heat-shock proteins. In conclusion, our preclinical data suggest that an appropriately timed sequential treatment of BRAF(V600) mutant melanoma with vemurafenib and adoptive T-cell transfer might result in synergistic antineoplastic effects owing to an increased immunogenicity of cancer cells.
authors.affiliation: Center for Cancer Immune Therapy; Department of Haematology; Copenhagen University Hospital at Herlev; Herlev, Denmark ; Department of Biomedical Sciences; University of Catania; Catania, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Donia
authors.forename: Paolo
authors.initials: P
authors.lastname: Fagone
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
authors.forename: Rikke Sick
authors.initials: RS
authors.lastname: Andersen
authors.forename: Estrid
authors.initials: E
authors.lastname: Høgdall
authors.forename: Per Thor
authors.initials: PT
authors.lastname: Straten
authors.forename: Mads Hald
authors.initials: MH
authors.lastname: Andersen
authors.forename: Inge Marie
authors.initials: IM
authors.lastname: Svane