Abstract 5561: High-affinity antisense oligonucleotides targeting Foxp3 inhibit immunosuppressive function of regulatory T-cells and produce antitumor effects in syngeneic tumor models
2018
Regulatory T-cells(Treg) contribute to cancer progression by suppressing anti-tumor immuity. Tregs specifically require expression of the lineage defining transcription factor
Foxp3for their development and function, but this protein cannot be targeted with conventional small molecule or biologic drugs. We employed next-generation antisense inhibitors (Gen 2.5 cEt-modified ASOs) in an attempt to selectively inhibit
Foxp3expression in mouse Treg cells, and evaluated consequences of ASO-mediated
Foxp3knock-down in vitro and in vivo. Mouse
Foxp3-specific ASOs promoted potent dose-dependent reductions in
Foxp3mRNA and protein in vitro, without the use of transfection reagents.
Foxp3knockdown also resulted in loss of immunosuppressive markers and conferred Tregs with a reduced immunosuppressive capacity. Whilst genetic ablation of
FOXP3leads to manifestation of autoimmunity due to a complete loss of Treg function, we observed that the systemic delivery of unformulated mouse
Foxp3ASOs to WT mice resulted in
Foxp3knockdown in vivo, but spared mice from an autoimmune phenotype. Nevertheless, when
syngeneictumor-bearing mice were treated with mouse
Foxp3ASOs tumor growth was significantly attenuated, with a fraction of animals (25%-50%) achieving complete regressions. Anti-tumor activity of mouse
Foxp3ASOs was associated with immunophenotypic changes consistent with an increased anti-tumor immune response. Overall these data demonstrate the therapeutic capacity of mouse ASO to directly target
regulatory T-cells, and suggesting that targeting of
Foxp3represents an attractive opportunity in
cancer immunotherapy. Citation Format: Charles Sinclair, Alexey S. Revenko, Alison Peter, Robert B. Johnson, Lisa A. Hettrick, Molly Taylor, Anna Staniszewska,
AdinaHughes, Lisa Sandin, Stephanie Klein, Andrew Watt, Simon Barry, Brett T. Monia, Paul Lyne, A Robert Macleod, Mark Edbrooke. High-affinity antisense oligonucleotides targeting
Foxp3inhibit immunosuppressive function of
regulatory T-cellsand produce antitumor effects in
syngeneictumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5561.
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