Prof. Dong-Ming Kuang’s team reported immunotherapy-elicited sialylation of IgG suppresses antitumorigenic type I IFN response in liver cancer
Source：Dong-Ming Kuang
2023-02-21
Recently, team of Professor Dong-Ming Kuang from Sun Yat-sen University presented a comprehensive study on how immune checkpoint blockade (ICB)-elicited IgG sialylation-mediated immunosuppression in tumors. The team found sialylated IgG were markedly induced in tumors during ICB of HCC patients, which led to type I IFN response defect via binding to type II Fc receptor DC-SIGN in tumor macrophages. Accordingly, the team suggested that HCC patients may be treated with immune checkpoint therapy in combination with IgG sialylation inhibition. This study, entitled “Immune checkpoint therapy-elicited sialylation of IgG antibodies impairs antitumorigenic type I interferon responses in hepatocellular carcinoma”, was published in Immunity on January 10, 2023.
Immune checkpoint therapy revitalizes and boosts the specific effector T cell response, and this approach has shed light on cancer therapy. However, the number of patients benefit from ICB is still limited e.g. overall response rate of advanced HCC patients to αPD-1 therapy is 20% only. Dissecting the complex immune response network involved in ICB will contribute to identify potential new targets and develop rational combinatorial therapeutic approaches. Antibody secreting cells are often located in the inflamed region of a tumor, which is also the aggregation site of effector T cells. Thus, an important issue that must be addressed in this context is whether the activation status of effector T cells orchestrates the nature of an antibody to accomplish a pathogenic effect and, if so, how immune checkpoint therapy might influence this interaction.
N-linked glycosylation is one of the predominant post-translational modifications involved in many biological functions. In IgG, N-linked glycosylation often occurs on the conserved asparagine at position 297 of the heavy chain of the CH2 constant domain in the Fc region. Under the catalysis of sialyltransferase ST6Gal-I or ST6Gal-II, N-linked glycans can undergo terminal sialylation, and this action makes the Fc region preferentially bind to type II Fc receptors DC-SIGN and CD23, rather than type I Fc receptors FcγRI, FcγRII, and FcγRIII. Many studies have demonstrated the importance of sialylated IgG in maintaining immune homeostasis. And yet, whether and how sialylated IgG participate in tumor progression are still elusive.
In this study, using tandem mass spectrometric analysis of modification of IgG from tumor tissues of liver cancer patients with or without immune checkpoint treatment, the authors identified a previously unrecognized role of ICB in catalyzing IgG sialylation in the Fc region. They demonstrated that effector T cells operate via interferon (IFN)-γ-ST6Gal-1-dependent pathways to stimulate sialylation of IgG. After engaging DC-SIGN+ macrophages, the main target cells for sialylated IgG in HCC tumors, sialylated IgG stimulates Raf-1-elicited upregulation of ATF3 via an antigen recognition-independent manner, which inactivates cGAS-STING pathway and eliminates subsequent type I IFN-triggered antitumorigenic immunity. More importantly, although enhanced IgG sialylation in tumors predicts improved therapeutic outcome of patients receiving anti-PD-1 treatment, impeding IgG sialylation augments antitumorigenic T cell immunity after immune checkpoint therapy.
Prof. Dong-Ming Kuang and Prof. Yuan Wei from School of Life Sciences, Sun Yat-sen University are co-corresponding authors. Dr. Rui-Qi Wu and Prof. Xiang-Ming Lao from Sun Yat-sen University Cancer Center, and Prof. Dong-Ping Chen from School of Life Sciences, Sun Yat-sen University are co-first authors. This study was greatly supported by Prof. Hongqiang Qin from Dalian Institute of Chemical Physics, CAS, Prof. Li Xu, Min-Shan Chen, and Limin Zheng from Sun Yat-sen University Cancer Center, and Porf. Qiang Gao from Zhongshan Hospital, Fudan University. This study was funded by project grants from the National Natural Science Foundation of China (82025016 and 31830025).
Article Links: https://www.sciencedirect.com/science/article/pii/S1074761322006045
Immune checkpoint therapy revitalizes and boosts the specific effector T cell response, and this approach has shed light on cancer therapy. However, the number of patients benefit from ICB is still limited e.g. overall response rate of advanced HCC patients to αPD-1 therapy is 20% only. Dissecting the complex immune response network involved in ICB will contribute to identify potential new targets and develop rational combinatorial therapeutic approaches. Antibody secreting cells are often located in the inflamed region of a tumor, which is also the aggregation site of effector T cells. Thus, an important issue that must be addressed in this context is whether the activation status of effector T cells orchestrates the nature of an antibody to accomplish a pathogenic effect and, if so, how immune checkpoint therapy might influence this interaction.
N-linked glycosylation is one of the predominant post-translational modifications involved in many biological functions. In IgG, N-linked glycosylation often occurs on the conserved asparagine at position 297 of the heavy chain of the CH2 constant domain in the Fc region. Under the catalysis of sialyltransferase ST6Gal-I or ST6Gal-II, N-linked glycans can undergo terminal sialylation, and this action makes the Fc region preferentially bind to type II Fc receptors DC-SIGN and CD23, rather than type I Fc receptors FcγRI, FcγRII, and FcγRIII. Many studies have demonstrated the importance of sialylated IgG in maintaining immune homeostasis. And yet, whether and how sialylated IgG participate in tumor progression are still elusive.
In this study, using tandem mass spectrometric analysis of modification of IgG from tumor tissues of liver cancer patients with or without immune checkpoint treatment, the authors identified a previously unrecognized role of ICB in catalyzing IgG sialylation in the Fc region. They demonstrated that effector T cells operate via interferon (IFN)-γ-ST6Gal-1-dependent pathways to stimulate sialylation of IgG. After engaging DC-SIGN+ macrophages, the main target cells for sialylated IgG in HCC tumors, sialylated IgG stimulates Raf-1-elicited upregulation of ATF3 via an antigen recognition-independent manner, which inactivates cGAS-STING pathway and eliminates subsequent type I IFN-triggered antitumorigenic immunity. More importantly, although enhanced IgG sialylation in tumors predicts improved therapeutic outcome of patients receiving anti-PD-1 treatment, impeding IgG sialylation augments antitumorigenic T cell immunity after immune checkpoint therapy.
Prof. Dong-Ming Kuang and Prof. Yuan Wei from School of Life Sciences, Sun Yat-sen University are co-corresponding authors. Dr. Rui-Qi Wu and Prof. Xiang-Ming Lao from Sun Yat-sen University Cancer Center, and Prof. Dong-Ping Chen from School of Life Sciences, Sun Yat-sen University are co-first authors. This study was greatly supported by Prof. Hongqiang Qin from Dalian Institute of Chemical Physics, CAS, Prof. Li Xu, Min-Shan Chen, and Limin Zheng from Sun Yat-sen University Cancer Center, and Porf. Qiang Gao from Zhongshan Hospital, Fudan University. This study was funded by project grants from the National Natural Science Foundation of China (82025016 and 31830025).
Article Links: https://www.sciencedirect.com/science/article/pii/S1074761322006045
