Synergistic effect of glutathione and IgG4 in immune evasion and the implication for cancer immunotherapy
Weifeng Zhang,
Yan Quan,
Xiaonan Ma,
Liting Zeng,
Jirui Li,
Shuqi Chen,
Meng Su,
Liangli Hong,
Penghao Li,
Hui Wang,
Qian Xu,
Chanyuan Zhao,
Xiaoqing Zhu,
Yiqun Geng,
Xiaomiao Yan,
Zheng Fang,
Muwang Chen,
Dongping Tian,
Min Su,
Xueling Chen,
Jiang Gu
Affiliations
Weifeng Zhang
Provincial Key Laboratory of Molecular Pathology and Personalized Medicine Center of Collaborative and Creative Center, Department of Pathology and Pathophysiology, Shantou University Medical College, Shantou, Guangdong, China
Yan Quan
The First Affiliated Hospital of Shantou University Medical College, Shantou, China
Xiaonan Ma
Provincial Key Laboratory of Molecular Pathology and Personalized Medicine Center of Collaborative and Creative Center, Department of Pathology and Pathophysiology, Shantou University Medical College, Shantou, Guangdong, China
Liting Zeng
Provincial Key Laboratory of Molecular Pathology and Personalized Medicine Center of Collaborative and Creative Center, Department of Pathology and Pathophysiology, Shantou University Medical College, Shantou, Guangdong, China
Jirui Li
Provincial Key Laboratory of Molecular Pathology and Personalized Medicine Center of Collaborative and Creative Center, Department of Pathology and Pathophysiology, Shantou University Medical College, Shantou, Guangdong, China
Shuqi Chen
Provincial Key Laboratory of Molecular Pathology and Personalized Medicine Center of Collaborative and Creative Center, Department of Pathology and Pathophysiology, Shantou University Medical College, Shantou, Guangdong, China
Meng Su
Provincial Key Laboratory of Molecular Pathology and Personalized Medicine Center of Collaborative and Creative Center, Department of Pathology and Pathophysiology, Shantou University Medical College, Shantou, Guangdong, China
Liangli Hong
Provincial Key Laboratory of Molecular Pathology and Personalized Medicine Center of Collaborative and Creative Center, Department of Pathology and Pathophysiology, Shantou University Medical College, Shantou, Guangdong, China; The First Affiliated Hospital of Shantou University Medical College, Shantou, China
Penghao Li
Provincial Key Laboratory of Molecular Pathology and Personalized Medicine Center of Collaborative and Creative Center, Department of Pathology and Pathophysiology, Shantou University Medical College, Shantou, Guangdong, China; Jinxin Research Institute for Reproductive Medicine and Genetics, Jinjiang Hospital for Maternal and Child Health Care, 66 Jingxiu Road, Chengdu, China
Hui Wang
Provincial Key Laboratory of Molecular Pathology and Personalized Medicine Center of Collaborative and Creative Center, Department of Pathology and Pathophysiology, Shantou University Medical College, Shantou, Guangdong, China
Qian Xu
Provincial Key Laboratory of Molecular Pathology and Personalized Medicine Center of Collaborative and Creative Center, Department of Pathology and Pathophysiology, Shantou University Medical College, Shantou, Guangdong, China
Chanyuan Zhao
Provincial Key Laboratory of Molecular Pathology and Personalized Medicine Center of Collaborative and Creative Center, Department of Pathology and Pathophysiology, Shantou University Medical College, Shantou, Guangdong, China
Xiaoqing Zhu
Provincial Key Laboratory of Molecular Pathology and Personalized Medicine Center of Collaborative and Creative Center, Department of Pathology and Pathophysiology, Shantou University Medical College, Shantou, Guangdong, China
Yiqun Geng
Provincial Key Laboratory of Molecular Pathology and Personalized Medicine Center of Collaborative and Creative Center, Department of Pathology and Pathophysiology, Shantou University Medical College, Shantou, Guangdong, China
Xiaomiao Yan
Jinxin Research Institute for Reproductive Medicine and Genetics, Jinjiang Hospital for Maternal and Child Health Care, 66 Jingxiu Road, Chengdu, China
Zheng Fang
Motic China Group Co, Ltd, Xiamen, China
Muwang Chen
Motic China Group Co, Ltd, Xiamen, China
Dongping Tian
Provincial Key Laboratory of Molecular Pathology and Personalized Medicine Center of Collaborative and Creative Center, Department of Pathology and Pathophysiology, Shantou University Medical College, Shantou, Guangdong, China
Min Su
Provincial Key Laboratory of Molecular Pathology and Personalized Medicine Center of Collaborative and Creative Center, Department of Pathology and Pathophysiology, Shantou University Medical College, Shantou, Guangdong, China
Xueling Chen
Provincial Key Laboratory of Molecular Pathology and Personalized Medicine Center of Collaborative and Creative Center, Department of Pathology and Pathophysiology, Shantou University Medical College, Shantou, Guangdong, China
Jiang Gu
Provincial Key Laboratory of Molecular Pathology and Personalized Medicine Center of Collaborative and Creative Center, Department of Pathology and Pathophysiology, Shantou University Medical College, Shantou, Guangdong, China; Jinxin Research Institute for Reproductive Medicine and Genetics, Jinjiang Hospital for Maternal and Child Health Care, 66 Jingxiu Road, Chengdu, China; Corresponding author. Shantou University Medical College, Department of Pathology, 22 Xinling Road, Shantou, 515031, China.
Background: We recently reported a novel IgG4-centered immune evasion mechanism in cancer, and this was achieved mostly through the Fc-Fc reaction of increased IgG4 to cancer-bound IgG in cancer microenvironment. The mechanism was suggested to be related to cancer hyperprogressive disease (HPD) which is a side-effect often associated to IgG4 subtype PD-1 antibody immunotherapy. HPD was reported to occur in cancers with certain mutated genes including KRAS and such mutations are often associated to glutathione (GSH) synthesis. Therefore, we hypothesize that IgG4 and GSH may play a synergistic role in local immunosuppression of cancer. Methods: Quantitatively analyzed the distribution and abundance of GSH and IgG4 in human cancer samples with ELISA and immunohistochemistry. The interactions between GSH and IgG4 were examined with Electrophoresis and Western Blot. The synergistic effects of the two on classic immune responses were investigated in vitro. The combined effects were also tested in a lung cancer model and a skin graft model in mice. Results: We detected significant increases of both GSH and IgG4 in the microenvironment of lung cancer, esophageal cancer, and colon cancer tissues. GSH disrupted the disulfide bond of IgG4 heavy chain and enhanced IgG4’s ability of Fc-Fc reaction to immobilized IgG subtypes. Combined administration of IgG4 and GSH augmented the inhibitory effect of IgG4 on the classic ADCC, ADCP, and CDC reactions. Local administration of IgG4/GSH achieved the most obvious effect of accelerating cancer growth in the mouse lung cancer model. The same combination prolonged the survival of skin grafts between two different strains of mouse. In both models, immune cells and several cytokines were found to shift to the state of immune tolerance. Conclusion: Combined application of GSH and IgG4 can promote tumor growth and protect skin graft. The mechanism may be achieved through the effect of the Fc-Fc reaction between IgG4 and other tissue-bound IgG subtypes resulting in local immunosuppression. This reaction was facilitated by increased GSH to dissociate the two heavy chains of IgG4 Fc fragment at its disulfide bonds. Our findings unveiled the interaction between the redox system and the immune systems in cancer microenvironment. It offers a sensible explanation for HPD and provides new possibilities for manipulating this mechanism for cancer immunotherapy.
