title: A peptide inhibitor of FOXP3 impairs regulatory T cell activity and improves vaccine efficacy in mice.
abstract: Immunosuppressive activity of regulatory T cells (Treg) may contribute to the progression of cancer or infectious diseases by preventing the induction of specific immune responses. Using a phage-displayed random peptide library, we identified a 15-mer synthetic peptide, P60, able to bind to forkhead/winged helix transcription factor 3 (FOXP3), a factor required for development and function of Treg. P60 enters the cells, inhibits FOXP3 nuclear translocation, and reduces its ability to suppress the transcription factors NF-κB and NFAT. In vitro, P60 inhibited murine and human-derived Treg and improved effector T cell stimulation. P60 administration to newborn mice induced a lymphoproliferative autoimmune syndrome resembling the reported pathology in scurfy mice lacking functional Foxp3. However, P60 did not cause toxic effects in adult mice and, when given to BALB/c mice immunized with the cytotoxic T cell epitope AH1 from CT26 tumor cells, it induced protection against tumor implantation. Similarly, P60 improved the antiviral efficacy of a recombinant adenovirus expressing NS3 protein from hepatitis C virus. Functional inhibition of Treg by the FOXP3-inhibitory peptide P60 constitutes a strategy to enhance antitumor and antiviral immunotherapies.
authors.affiliation: Gene Therapy and Hepatology Area, University of Navarra, Pamplona, Spain.
authors.forename: Noelia
authors.initials: N
authors.lastname: Casares
authors.forename: Francesc
authors.initials: F
authors.lastname: Rudilla
authors.forename: Laura
authors.initials: L
authors.lastname: Arribillaga
authors.forename: Diana
authors.initials: D
authors.lastname: Llopiz
authors.forename: José Ignacio
authors.initials: JI
authors.lastname: Riezu-Boj
authors.forename: Teresa
authors.initials: T
authors.lastname: Lozano
authors.forename: Jacinto
authors.initials: J
authors.lastname: López-Sagaseta
authors.forename: Laura
authors.initials: L
authors.lastname: Guembe
authors.forename: Pablo
authors.initials: P
authors.lastname: Sarobe
authors.forename: Jesús
authors.initials: J
authors.lastname: Prieto
authors.forename: Francisco
authors.initials: F
authors.lastname: Borrás-Cuesta
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Lasarte
mesh_terms: D000818:Animals; D005260:Female; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D018613:Microscopy, Confocal; D019151:Peptide Library; D010455:Peptides / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D014162:Transfection; D014612:Vaccines / Q000276:immunology*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D019151:Peptide Library; D010455:Peptides; D014612:Vaccines