A peptide inhibitor of FOXP3 impairs regulatory T cell activity and improves vaccine efficacy in mice.
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.
Casares
Noelia
N
Gene Therapy and Hepatology Area, University of Navarra, Pamplona, Spain.
Rudilla
Francesc
F
Arribillaga
Laura
L
Llopiz
Diana
D
Riezu-Boj
José Ignacio
JI
Lozano
Teresa
T
López-Sagaseta
Jacinto
J
Guembe
Laura
L
Sarobe
Pablo
P
Prieto
Jesús
J
Borrás-Cuesta
Francisco
F
Lasarte
Juan José
JJ
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*
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D019151:Peptide Library; D010455:Peptides; D014612:Vaccines