title: Immunomodulatory pathways regulate expression of a spliced FKBP51 isoform in lymphocytes of melanoma patients.
abstract: FKBP51 (gene FKBP5) is an immunophilin capable of immunosuppression expressed in melanoma and lymphocytes. We found increased levels of a spliced FKBP5 variant in the PBMCs of 124 patients with melanoma. This variant encodes for an unknown isoform (FKBP51s). We hypothesized that FKBP51s resulted from tumour interaction with immune cells, through PDL-1/PD-1. To address this issue, we performed melanoma/PBMC cocultures. Furthermore, the immunohistochemistry of 76 melanoma specimens served to investigate whether FKBP51s stained tumour infiltrating lymphocytes. Our results showed that PBMCs expressed FKBP51s when cocultured with melanoma. Tumour PDL-1 knockdown or anti-PD-1 reduced FKBP51s expression in cocultured PBMCs. IHC showed a strong FKBP51s signal in tumour infiltrating lymphocytes, and lymphocytes of the invasion front of the tumour, along with melanoma PDL-1 expression. When overexpressed in melanoma, FKBP51s facilitated PDL-1 expression on the cell surface. In conclusion, our study shows that FKBP51s marks the PBMCs of patients with melanoma and is exploited by the tumour to immunomodulate through PDL-1.
authors.affiliation: Department of Molecular Medicine and Medical Biotechnologies, Federico II University, Naples, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Romano
authors.affiliation: Department of Molecular Medicine and Medical Biotechnologies, Federico II University, Naples, Italy.|Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: D'Angelillo
authors.affiliation: Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Staibano
authors.affiliation: Melanoma Unit, National Cancer Institute 'G. Pascale Foundation', Naples, Italy.
authors.forename: Ester
authors.initials: E
authors.lastname: Simeone
authors.affiliation: Department of Molecular Medicine and Medical Biotechnologies, Federico II University, Naples, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: D'Arrigo
authors.affiliation: Melanoma Unit, National Cancer Institute 'G. Pascale Foundation', Naples, Italy.
authors.forename: Paolo Antonio
authors.initials: PA
authors.lastname: Ascierto
authors.affiliation: Dermatology Section, Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Scalvenzi
authors.affiliation: Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Mascolo
authors.affiliation: Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy.
authors.forename: Gennaro
authors.initials: G
authors.lastname: Ilardi
authors.affiliation: Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Merolla
authors.affiliation: Department of Biological Science, University of Portsmouth, Portsmouth, UK.
authors.forename: Egle
authors.initials: E
authors.lastname: Jovarauskaite
authors.affiliation: Department of Molecular Medicine and Medical Biotechnologies, Federico II University, Naples, Italy.
authors.forename: Maria Fiammetta
authors.initials: MF
authors.lastname: Romano
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017398:Alternative Splicing / Q000235:genetics*; D060890:B7-H1 Antigen / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007155:Immunologic Factors / Q000378:metabolism*; D008214:Lymphocytes / Q000378:metabolism*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D008875:Middle Aged; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics; D055815:Young Adult; D000099159:Tacrolimus Binding Protein 5
chemical_list: D060890:B7-H1 Antigen; D007155:Immunologic Factors; D020033:Protein Isoforms; D022021:Tacrolimus Binding Proteins; D016212:Transforming Growth Factor beta; D000099159:Tacrolimus Binding Protein 5; C423236:CD274 protein, human
keywords: FKBP51 spliced isoform; PDL-1; immune signature; lymphocytes; melanoma