{"id":"doi:10.1038/s41422-020-00395-4","kind":"article","title":"Manganese is critical for antitumor immune responses via cGAS-STING and improves the efficacy of clinical immunotherapy","authors":["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"],"author_count":16,"year":2020,"published":"2020-08-24","venue":"Cell Research","cited_by":1040,"doi":"10.1038/s41422-020-00395-4","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1038/s41422-020-00395-4","archive_url":"https://space-kitty.com/papers/doi:10.1038/s41422-020-00395-4","updated":null,"pmid":"32839553","pmcid":null,"openalex_id":"W3080399909","pdf_url":"https://www.nature.com/articles/s41422-020-00395-4.pdf","abstract":"Abstract 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.","abstract_license":"CC-BY (publisher license, via OpenAlex)","license":"cc-by","is_open_access":true,"peer_reviewed":null,"categories":["Cancer Immunotherapy and Biomarkers"],"details":null,"provenance":"openalex","attribution":"Abstract of \"Manganese is critical for antitumor immune responses via cGAS-STING and improves the efficacy of clinical immunotherapy\" by Mengze Lv, Meixia Chen, Rui Zhang et al., https://doi.org/10.1038/s41422-020-00395-4, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified.","topics":[{"slug":"cancer-immunotherapy","name":"Cancer Immunotherapy","domain_slug":"medicine"}],"cited_in_dossiers":[]}