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 prote...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.展开更多
Coronavirus disease 2019(COVID-19)is an acute respiratory infectious disease caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection.It is highly contagious and can cause death in severe cases.A...Coronavirus disease 2019(COVID-19)is an acute respiratory infectious disease caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection.It is highly contagious and can cause death in severe cases.As reported by the World Health Organization(WHO),as of 6:36 pm Central European Summer Time(CEST),12 August 2022,there had been 585950285 confirmed cases of COVID-19,including 6425422 deaths(WHO,2022).According to previous studies,healthcare workers(HCWs)have a higher risk of developing COVID-19 compared with the general community,and the severity of COVID-19 is closely related to the health-related effects after discharge(Huang et al.,2021).展开更多
基金supported by the National Natural Science Foundation of China(82071803,82241217,and 82271811)Fundamental Research Funds for the Central Universities(2021GCRC037)Project Funded by China Postdoctoral Science Foundation(2021M691155).
文摘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.
基金supported by the Rehabilitation Care Project for Medical Staff Infected with COVID-19 in China launching by Chinese Academy of Engineering and Tencent Foundation.
文摘Coronavirus disease 2019(COVID-19)is an acute respiratory infectious disease caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection.It is highly contagious and can cause death in severe cases.As reported by the World Health Organization(WHO),as of 6:36 pm Central European Summer Time(CEST),12 August 2022,there had been 585950285 confirmed cases of COVID-19,including 6425422 deaths(WHO,2022).According to previous studies,healthcare workers(HCWs)have a higher risk of developing COVID-19 compared with the general community,and the severity of COVID-19 is closely related to the health-related effects after discharge(Huang et al.,2021).
