BFAR coordinates TGFβ signaling to modulate Th9-mediated cancer immunotherapy.
Adaptor Proteins, Signal Transducing
/ immunology
Animals
Apoptosis Regulatory Proteins
/ immunology
Cell Differentiation
/ immunology
Down-Regulation
/ immunology
Humans
Immunotherapy
/ methods
Membrane Proteins
/ immunology
Mice
Mice, Inbred C57BL
Mice, Knockout
Neoplasms
/ immunology
Signal Transduction
/ immunology
T-Lymphocytes, Helper-Inducer
/ immunology
Transforming Growth Factor beta
/ immunology
Journal
The Journal of experimental medicine
ISSN: 1540-9538
Titre abrégé: J Exp Med
Pays: United States
ID NLM: 2985109R
Informations de publication
Date de publication:
05 07 2021
05 07 2021
Historique:
received:
05
10
2020
revised:
25
01
2021
accepted:
04
03
2021
entrez:
29
4
2021
pubmed:
30
4
2021
medline:
13
10
2021
Statut:
ppublish
Résumé
TGFβ 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 TGFβ signaling in Th9-mediated cancer immunotherapy remains elusive. Here, we find that TGFβ-induced down-regulation of bifunctional apoptosis regulator (BFAR) represents the key mechanism preventing the sustained activation of TGFβ signaling and thus impairing Th9 inducibility. Mechanistically, BFAR mediates K63-linked ubiquitination of TGFβR1 at K268, which is critical to activate TGFβ signaling. Thus, BFAR deficiency or K268R knock-in mutation suppresses TGFβR1 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 TGFβ-regulated gene to fine-tune TGFβ signaling that causes Th9 induction insensitivity, and they highlight the translational potential of BFAR in promoting Th9-mediated cancer immunotherapy.
Identifiants
pubmed: 33914044
pii: 212036
doi: 10.1084/jem.20202144
pmc: PMC8091105
pii:
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Apoptosis Regulatory Proteins
0
BFAR protein, human
0
Membrane Proteins
0
Transforming Growth Factor beta
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2021 Pei et al.
Déclaration de conflit d'intérêts
Disclosures: The authors declare no competing interests exist.
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