Synergistic effect of glutathione and IgG4 in immune evasion and the implication for cancer immunotherapy.
Synergistic effect of glutathione and IgG4 in immune evasion and the implication for cancer immunotherapy.
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谷胱甘肽和 IgG4 在免疫逃避中的协同作用及其对癌症免疫治疗的意义
DOI：
10.1016/j.redox.2023.102608
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发表时间：
2023-04
期刊：
影响因子：
11.4
通讯作者：
Gu, Jiang
中科院分区：
文献类型：
--
作者：
Zhang, Weifeng;Quan, Yan;Ma, Xiaonan;Zeng, Liting;Li, Jirui;Chen, Shuqi;Su, Meng;Hong, Liangli;Li, Penghao;Wang, Hui;Xu, Qian;Zhao, Chanyuan;Zhu, Xiaoqing;Geng, Yiqun;Yan, Xiaomiao;Fang, Zheng;Chen, Muwang;Tian, Dongping;Su, Min;Chen, Xueling;Gu, Jiang
关键词：
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. 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. 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. 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.
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影响因子：
11.2
作者：
Galan-Cobo, Ana;Sitthideatphaiboon, Piyada;Heymach, John, V
通讯作者：
Heymach, John, V
DOI：
10.1158/1078-0432.ccr-16-3133
发表时间：
2017-08-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Kato S;Goodman A;Walavalkar V;Barkauskas DA;Sharabi A;Kurzrock R
通讯作者：
Kurzrock R
IgG4将M2A巨噬细胞驱动到调节性M2B样表型：对免疫耐受性的潜在影响。
影响因子：
12.4
作者：
Bianchini R;Roth-Walter F;Ohradanova-Repic A;Flicker S;Hufnagl K;Fischer MB;Stockinger H;Jensen-Jarolim E
通讯作者：
Jensen-Jarolim E
影响因子：
7.2
作者：
Jordakieva G;Bianchini R;Reichhold D;Piehslinger J;Groschopf A;Jensen SA;Mearini E;Nocentini G;Crevenna R;Zlabinger GJ;Karagiannis SN;Klaus A;Jensen-Jarolim E
通讯作者：
Jensen-Jarolim E
影响因子：
56.9
作者：
Kolfschoten, Marijn van der Neut;Schuurman, Janine;Parren, Paul W. H. I.
通讯作者：
Parren, Paul W. H. I.