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BFAR coordinates TGFβ signaling to modulate Th9-mediated cancer immunotherapy.
- Source :
-
The Journal of experimental medicine [J Exp Med] 2021 Jul 05; Vol. 218 (7). - Publication Year :
- 2021
-
Abstract
- 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.<br />Competing Interests: Disclosures: The authors declare no competing interests exist.<br /> (© 2021 Pei et al.)
- Subjects :
- Animals
Cell Differentiation immunology
Down-Regulation immunology
Humans
Immunotherapy methods
Mice
Mice, Inbred C57BL
Mice, Knockout
T-Lymphocytes, Helper-Inducer immunology
Adaptor Proteins, Signal Transducing immunology
Apoptosis Regulatory Proteins immunology
Membrane Proteins immunology
Neoplasms immunology
Neoplasms therapy
Signal Transduction immunology
Transforming Growth Factor beta immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1540-9538
- Volume :
- 218
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- The Journal of experimental medicine
- Publication Type :
- Academic Journal
- Accession number :
- 33914044
- Full Text :
- https://doi.org/10.1084/jem.20202144