title: Depleting regulatory T cells with arginine-rich, cell-penetrating, peptide-conjugated morpholino oligomer targeting FOXP3 inhibits regulatory T-cell function.
abstract: CD4+CD25+regulatory T cells (T(reg)) impair anti-tumor and anti-viral immunity. As there are higher T(reg) levels in cancer patients compared with healthy individuals, there is considerable interest in eliminating them or altering their function as part of cancer or viral immunotherapy strategies. The scurfin transcriptional regulator encoded by the member of the forkhead winged helix protein family (FOXP3) is critical for maintaining the functions of T(reg). We hypothesized that targeting FOXP3 expression with a novel arginine-rich, cell-penetrating, peptide-conjugated phosphorodiamidate morpholino (PPMO) based antisense would eliminate T(reg) and enhance the induction of effector T-cell responses. We observed that the PPMO was taken up by activated T cells in vitro and could downregulate FOXP3 expression, which otherwise increases during antigen-specific T-cell activation. Generation of antigen-specific T cells in response to peptide stimulation was enhanced by pre-treatment of peripheral blood mononuclear cells with the FOXP3-targeted PPMO. In summary, modulation of T(reg) levels using the FOXP3 PPMO antisense-based genomic strategy has the potential to optimize immunotherapy strategies in cancer and viral immunotherapy.
authors: Duke Comprehensive Cancer Center, Duke University Medical Center, Durham, NC 27710, USA.
authors: M A
authors: MA
authors: Morse
authors: A
authors: A
authors: Hobeika
authors: D
authors: D
authors: Serra
authors: K
authors: K
authors: Aird
authors: M
authors: M
authors: McKinney
authors: A
authors: A
authors: Aldrich
authors: T
authors: T
authors: Clay
authors: D
authors: D
authors: Mourich
authors: H K
authors: HK
authors: Lyerly
authors: P L
authors: PL
authors: Iversen
authors: G R
authors: GR
authors: Devi
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D060172:Morpholinos / Q000235:genetics / Q000493:pharmacokinetics / Q000494:pharmacology*; D009369:Neoplasms / Q000097:blood / Q000276:immunology; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000493:pharmacokinetics / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D060172:Morpholinos; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger