BFAR coordinates TGFβ signaling to modulate Th9-mediated cancer immunotherapy

TGF beta 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 TGF beta signaling in Th9mediated cancer immunotherapy remains elusive. Here, we find that TGF beta-induced down-regulation of bifunctional apoptosis regulator (BFAR) represents the key mechanism preventing the sustained activation of TGF beta signaling and thus impairing Th9 inducibility. Mechanistically, BFAR mediates K63-linked ubiquitination of TGFI3R1 at K268, which is critical to activate TGF beta signaling. Thus, BFAR deficiency or K268R knock-in mutation suppresses TGF beta R1 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 TGF beta-regulated gene to fine-tune TGF beta signaling that causes Th9 induction insensitivity, and they highlight the translational potential of BFAR in promoting Th9-mediated cancer immunotherapy.

Automated summary

The study reveals that down-regulation of BFAR induced by TGFβ is a key mechanism affecting Th9 induction, which in turn impacts Th9-mediated cancer immunotherapy by regulating the activation of TGFβ signaling pathway.