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| 1 | Manganese is critical for antitumor immune responses via cGAS-STING and improves the efficacy of clinical immunotherapy显示文摘CD8^+T cell-mediated cancer clearance is often suppressed by the interaction between inhibitory molecules like PD-1 and PD-L1,an interaction acts like brakes to prevent T cell overreaction under normal conditions but is exploited by tumor cells to escape the immune surveillance.Immune checkpoint inhibitors have revolutionized cancer therapeutics by removing such brakes.Unfortunately,only a minority of cancer patients respond to immunotherapies presumably due to inadequate immunity.Antitumor immunity depends on the activation of the cGAS-STING pathway,as STING-deficient mice fail to stimulate tumor-infiltrating dendritic cells(DCs)to activate CD8^+T cells.STING agonists also enhance natural killer(NK)cells to mediate the clearance of CD8^+T cell-resistant tumors.Therefore STING agonists have been intensively sought after.We previously discovered that manganese(Mn)is indispensable for the host defense against cytosolic dsDNA by activating cGAS-STING.Here we report that Mn is also essential in innate immune sensing of tumors and enhances adaptive immune responses against tumors.Mn-insufficient mice had significantly enhanced tumor growth and metastasis,with greatly reduced tumor-infiltrating CD8^+T cells.Mechanically,Mn^2+promoted DC and macrophage maturation and tumor-specific antigen presentation,augmented CD8^+T cell differentiation,activation and NK cell activation,and increased memory CD8^+T cells.Combining Mn^2+with immune checkpoint inhibition synergistically boosted antitumor efficacies and reduced the anti-PD-1 antibody dosage required in mice.Importantly,a completed phase 1 clinical trial with the combined regimen of Mn^2+and anti-PD-1 antibody showed promising efficacy,exhibiting type I IFN induction,manageable safety and revived responses to immunotherapy in most patients with advanced metastatic solid tumors.We propose that this combination strategy warrants further clinical translation. | Mengze Lv Meixia Chen Rui Zhang Wen Zhang Chenguang Wang Yan Zhang Xiaoming Wei Yukun Guan Jiejie Liu Kaichao Feng Miao Jing Xurui Wang Yun-Cai Liu Qian Mei Weidong Han Zhengfan Jiang | 2020 | Cell Research2020，30，11： | 27 |
| 2 | Manganese salts function as potent adjuvants显示文摘Aluminum-containing adjuvants have been used for nearly 100 years to enhance immune responses in billions of doses of vaccines.To date,only a few adjuvants have been approved for use in humans,among which aluminum-containing adjuvants are the only ones widely used.However,the medical need for potent and safe adjuvants is currently continuously increasing,especially those triggering cellular immune responses for cytotoxic T lymphocyte activation,which are urgently needed for the development of efficient virus and cancer vaccines.Manganese is an essential micronutrient required for diverse biological activities,but its functions in immunity remain undefined.We previously reported that Mn^(2+) is important in the host defense against cytosolic dsDNA by facilitating cGAS-STING activation and that Mn^(2+)alone directly activates cGAS independent of dsDNA,leading to an unconventional catalytic synthesis of 2′3′-cGAMP.Herein,we found that Mn^(2+) strongly promoted immune responses by facilitating antigen uptake,presentation,and germinal center formation via both cGAS-STING and NLRP3 activation.Accordingly,a colloidal manganese salt(Mn jelly,MnJ)was formulated to act not only as an immune potentiator but also as a delivery system to stimulate humoral and cellular immune responses,inducing antibody production and CD4^(+)/CD8^(+)T-cell proliferation and activation by either intramuscular or intranasal immunization.When administered intranasally,MnJ also worked as a mucosal adjuvant,inducing high levels of secretory IgA.MnJ showed good adjuvant effects for all tested antigens,including T cell-dependent and T cell-independent antigens,such as bacterial capsular polysaccharides,thus indicating that it is a promising adjuvant candidate. | Rui Zhang Chenguang Wang Yukun Guan Xiaoming Wei Mengyin Sha Mengran Yi Miao Jing Mengze Lv Wen Guo Jing Xu Yi Wan Xin-Ming Jia Zhengfan Jiang | 2021 | Cellular & Molecular Immunology2021，18，5： | 7 |
| 3 | Manganese enhances the antitumor function of CD8^(+)T cells by inducing type I interferon production显示文摘The presence of cytosolic DNA at tumor sites and the activation of the cGAS-STING pathway have been implicated in the activation of antitumor immune responses.1,2,3 Manganese (Mn) is a necessary trace element for intracellular activities. It plays important roles in development, digestion, reproduction, antioxidant defense, energy production, immunity, and neuronal activity regulation.4 Mn was reported to enhance cGAS-STING activation through increased sensitivity to dsDNA during viral infections.5 However, it is unclear whether Mn can enhance antitumor immune functions. Here, we revealed that Mn2+ could inhibit the development of murine hepatocellular carcinoma (HCC) through immune modulations. It upregulated IFN-γ and TNF-α production in splenic and tumor-infiltrating CD8+ T cells. Moreover, Mn2+ significantly increased type I interferon (IFN) production and type I IFN-stimulated gene (ISG) expression in tumor-bearing mice. Further analysis revealed that myeloid cells could upregulate type I IFN production and increase costimulatory molecule expression upon Mn2+ stimulation. In vivo depletion of CD8+ T cells or treatment of IFNAR KO mice diminished the antitumor activity of Mn2+, suggesting that the antitumor function of Mn2+ is dependent on both CD8+ T cells and type I IFN signaling. Our results provide evidence to support Mn2+ as a novel agent that can be incorporated into cancer immunotherapy. | Yuan Song Yonghao Liu Huey Yee Teo Zuhairah Binte Hanafi Yu Mei Ying Zhu Yen Leong Chua Mengze Lv Zhengfan Jiang Haiyan Liu | 2021 | Cellular & Molecular Immunology2021，18，6： | 1 |
| 4 | 锰增加双链DNA的cGAS-STING通路的敏感度并为宿主防御DNA病毒所需要显示文摘文章简介通过分析细胞培养基不同组分对细胞抗病毒能力的影响,课题组意外发现Mn2+可以强烈激活细胞内的cGASSTING通路,使细胞获得很强的抗病毒能力。 | 王晨光 管玉坤 Mengze Lv Rui Zhang Zhaoying Guo Xiaoming Wei Xiaoxia Du Jing Yang Tong Li 万祎 苏晓东 黄晓军 蒋争凡 | 2019 | 科学新闻2019，0，2： | 0 |
| 5 | 炎症小体通过活化蛋白酶Caspase-1切割细胞内DNA受体cGAS调节细胞对DNA病毒感染的反应显示文摘文章简介DNA病毒感染引起宿主的天然免疫反应,可同时激活两条重要的信号通路——I型干扰素通路(Type I-IFN)和炎性小体通路(Inflammasome)。一方面,宿主细胞的DNA受体cG AS能识别病毒的DNA,并催化第二信使cG AMP的合成。 | 王宇涛 宁小涵 Pengfei Gao Shuxian Wu Mengyin Sha Mengze Lv Xiang Zhou Juyi Gao Run Fang 孟广勋 苏晓东 蒋争凡 | 2018 | 科学新闻2018，0，4： | 0 |
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