BFAR coordinates TGFß signaling to modulate Th9-mediated cancer immunotherapy.
J Exp Med
; 218(7)2021 07 05.
Article
em En
| MEDLINE
| ID: mdl-33914044
ABSTRACT
TGFß is essential for the generation of anti-tumor Th9 cells; on the other hand, it causes resistance against anti-tumor immunity. Despite recent progress, the underlying mechanism reconciling the double-edged effect of TGFß signaling in Th9-mediated cancer immunotherapy remains elusive. Here, we find that TGFß-induced down-regulation of bifunctional apoptosis regulator (BFAR) represents the key mechanism preventing the sustained activation of TGFß signaling and thus impairing Th9 inducibility. Mechanistically, BFAR mediates K63-linked ubiquitination of TGFßR1 at K268, which is critical to activate TGFß signaling. Thus, BFAR deficiency or K268R knock-in mutation suppresses TGFßR1 ubiquitination and Th9 differentiation, thereby inhibiting Th9-mediated cancer immunotherapy. More interestingly, BFAR-overexpressed Th9 cells exhibit promising therapeutic efficacy to curtail tumor growth and metastasis and promote the sensitivity of anti-PD-1-mediated checkpoint immunotherapy. Thus, our findings establish BFAR as a key TGFß-regulated gene to fine-tune TGFß signaling that causes Th9 induction insensitivity, and they highlight the translational potential of BFAR in promoting Th9-mediated cancer immunotherapy.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
/
Fator de Crescimento Transformador beta
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Proteínas Adaptadoras de Transdução de Sinal
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Proteínas Reguladoras de Apoptose
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Proteínas de Membrana
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Neoplasias
Limite:
Animals
/
Humans
Idioma:
En
Revista:
J Exp Med
Ano de publicação:
2021
Tipo de documento:
Article