Targeting TNFR2 with antagonistic antibodies inhibits proliferation of ovarian cancer cells and tumor-associated Tregs.
Sci Signal
; 10(462)2017 01 17.
Article
en En
| MEDLINE
| ID: mdl-28096513
ABSTRACT
Major barriers to cancer therapy include the lack of selective inhibitors of regulatory T cells (Tregs) and the lack of broadly applicable ways to directly target tumors through frequently expressed surface oncogenes. Tumor necrosis factor receptor 2 (TNFR2) is an attractive target protein because of its restricted abundance to highly immunosuppressive Tregs and oncogenic presence on human tumors. We characterized the effect of TNFR2 inhibition using antagonistic antibodies. In culture-based assays, we found that two TNFR2 antagonists inhibited Treg proliferation, reduced soluble TNFR2 secretion from normal cells, and enabled T effector cell expansion. The antagonistic activity occurred in the presence of added TNF, a natural TNFR2 agonist. These TNFR2 antibodies killed Tregs isolated from ovarian cancer ascites more potently than it killed Tregs from healthy donor samples, suggesting that these antibodies may have specificity for the tumor microenvironment. The TNFR2 antagonists also killed OVCAR3 ovarian cancer cells, which have abundant surface TNFR2. The antibodies stabilized antiparallel dimers in cell surface TNFR2 that rendered the receptor unable to activate the nuclear factor κB pathway and trigger cell proliferation. Our data suggest that, by targeting tumor cells and immunosuppressive tumor-associated Tregs, antagonistic TNFR2 antibodies may be an effective treatment for cancers positive for TNFR2.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Linfocitos T Reguladores
/
Receptores Tipo II del Factor de Necrosis Tumoral
/
Proliferación Celular
/
Anticuerpos Monoclonales
Tipo de estudio:
Risk_factors_studies
Límite:
Female
/
Humans
Idioma:
En
Revista:
Sci Signal
Asunto de la revista:
CIENCIA
/
FISIOLOGIA
Año:
2017
Tipo del documento:
Article
País de afiliación:
Estados Unidos