TGF-ß and VEGF cooperatively control the immunotolerant tumor environment and the efficacy of cancer immunotherapies.
JCI Insight
; 1(9): e85974, 2016 06 16.
Article
en En
| MEDLINE
| ID: mdl-27699271
ABSTRACT
Tregs imprint an early immunotolerant tumor environment that prevents effective antitumor immune responses. Using transcriptomics of tumor tissues, we identified early upregulation of VEGF and TGF-ß pathways compatible with tolerance imprinting. Silencing of VEGF or TGF-ß in tumor cells induced early and pleiotropic modulation of immune-related transcriptome signatures in tumor tissues. These were surprisingly similar for both silenced tumors and related to common downstream effects on Tregs. Silencing of VEGF or TGF-ß resulted in dramatically delayed tumor growth, associated with decreased Tregs and myeloid-derived suppressor cells and increased effector T cell activation in tumor infiltrates. Strikingly, co-silencing of TGF-ß and VEGF led to a substantial spontaneous tumor eradication rate and the combination of their respective inhibitory drugs was synergistic. VEGF and/or TGF-ß silencing also restored tumor sensitivity to tumor-specific cell therapies and markedly improved the efficacy of anti-PD-1/anti-CTLA-4 treatment. Thus, TGF-ß and VEGF cooperatively control the tolerant environment of tumors and are targets for improved cancer immunotherapies.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Factor de Crecimiento Transformador beta
/
Silenciador del Gen
/
Factor A de Crecimiento Endotelial Vascular
/
Inmunoterapia
/
Neoplasias
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
JCI Insight
Año:
2016
Tipo del documento:
Article
País de afiliación:
Francia