Abstract
Immune checkpoint blockade (ICB), including anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4), benefits only a limited number of patients with cancer. Understanding the in-depth regulatory mechanism of CTLA-4 protein stability and its functional significance may help identify ICB resistance mechanisms and assist in the development of novel immunotherapeutic modalities to improve ICB efficacy. Here, we identified that TNF receptor-associated factor 6 (TRAF6) mediates Lys63-linked ubiquitination and subsequent lysosomal degradation of CTLA-4. Moreover, by using TRAF6-deficient mice and retroviral overexpression experiments, we demonstrated that TRAF6 promotes CTLA-4 degradation in a T-cell-intrinsic manner, which is dependent on the RING domain of TRAF6. This intrinsic regulatory mechanism contributes to CD8(+) T-cell-mediated antitumor immunity in vivo. Additionally, by using an OX40 agonist, we demonstrated that the OX40-TRAF6 axis is responsible for CTLA-4 degradation, thereby controlling antitumor immunity in both tumor-bearing mice and patients with cancer. Overall, our findings demonstrate that the OX40-TRAF6 axis promotes CTLA-4 degradation and is a potential therapeutic target for the improvement of T-cell-based immunotherapies.