| First Author | Pei S | Year | 2021 |
| Journal | J Exp Med | Volume | 218 |
| Issue | 7 | PubMed ID | 33914044 |
| Mgi Jnum | J:343892 | Mgi Id | MGI:6724850 |
| Doi | 10.1084/jem.20202144 | Citation | Pei S, et al. (2021) BFAR coordinates TGFbeta signaling to modulate Th9-mediated cancer immunotherapy. J Exp Med 218(7) |
| abstractText | TGFbeta 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 TGFbeta signaling in Th9-mediated cancer immunotherapy remains elusive. Here, we find that TGFbeta-induced down-regulation of bifunctional apoptosis regulator (BFAR) represents the key mechanism preventing the sustained activation of TGFbeta signaling and thus impairing Th9 inducibility. Mechanistically, BFAR mediates K63-linked ubiquitination of TGFbetaR1 at K268, which is critical to activate TGFbeta signaling. Thus, BFAR deficiency or K268R knock-in mutation suppresses TGFbetaR1 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 TGFbeta-regulated gene to fine-tune TGFbeta signaling that causes Th9 induction insensitivity, and they highlight the translational potential of BFAR in promoting Th9-mediated cancer immunotherapy. |
