Manganese is critical for antitumor immune responses via cGAS-STING and improves the efficacy of clinical immunotherapy

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 in...

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Published in:	Cell research 2020-11, Vol.30 (11), p.966-979
Main Authors:	Lv, Mengze, Chen, Meixia, Zhang, Rui, Zhang, Wen, Wang, Chenguang, Zhang, Yan, Wei, Xiaoming, Guan, Yukun, Liu, Jiejie, Feng, Kaichao, Jing, Miao, Wang, Xurui, Liu, Yun-Cai, Mei, Qian, Han, Weidong, Jiang, Zhengfan
Format:	Article
Language:	eng
Subjects:	Adaptive immunity Agonists Antibodies Antigen presentation Antigens Antitumor activity Brakes Cancer CD8 antigen Cell activation Cell differentiation Dendritic cells Differentiation (biology) Immune checkpoint inhibitors Immune clearance Immunity Immunological memory Immunosurveillance Immunotherapy Interferon Lymphocytes Lymphocytes T Macrophages Manganese Memory cells Metastases Natural killer cells PD-1 protein PD-L1 protein Safety management Solid tumors Tumor cells Tumors
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Summary:	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 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 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 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.
ISSN:	1001-0602 1748-7838