BFAR coordinates TGFβ signaling to modulate Th9-mediated cancer immunotherapy

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.

The Love-Hate Relationship Between TGF-β Signaling and the Immune System During Development and Tumorigenesis

“…In addition, a recent study by Yichuan Xiao's group reported that TGF-b collaborates with BFAR (a bifunctional apoptosis regulator) to regulate the antitumor function of Th9 cells, as BFAR-overexpressing Th9 cells display favorable antitumor efficacy. By contrast, BFAR KO significantly inhibits TGF-bR1 ubiquitination and Th9 differentiation, hence inhibiting the antitumor function of Th9 cells (61). Taken together, the above studies emphasize the importance of TGF-b in Th9 cell differentiation and function.…”

Enhancement of T cell infiltration via tumor-targeted Th9 cell delivery improves the efficacy of antitumor immunotherapy of solid tumors

“…Recent studies emphasized that Th9-induced tumor eradication relied on IL-9 and IL-9 had an important impact on the composition of immune cells in tumors, including CD8 + T cells ([ 32 , 35 , 38 , 39 ]). Thus, we sought to determine whether IL-9 was involved in the tumor rejection of osteosarcoma after the tumor-specific Th9-KTP transfusion by using an IL-9 neutralizing antibody (α-IL-9) while the control group was administrated with IgG2a.…”

Identification of Potential Immune Checkpoint Inhibitor Targets in Gliomas via Bioinformatic Analyses

“…Immunotherapy is increasingly being considered as a potential treatment for gliomas, especially with immune checkpoint inhibitors (ICIs). The currently approved checkpoint inhibitors block PD-1/PD-L1 and CTLA4 and have been tested in multiple cancers, including breast cancer [ 14 , 15 ], lung cancer [ 16 , 17 ], and skin cancer [ 18 , 19 ]. However, ICIs have achieved limited results against brain cancer including GBM and LGG, and only 10% of GBM patients benefit from immunotherapy [ 20 ].…”