Volume 30, No 11, Nov 2020

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 30 Issue 11, November 2020: 966-979   |  Open Access

ORIGINAL ARTICLES

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

Mengze Lv^1,2,5 , Meixia Chen³ , Rui Zhang^1,2 , Wen Zhang^4,5 , Chenguang Wang^1,2 , Yan Zhang³ , Xiaoming Wei^1,2 , Yukun Guan^1,2,6 , Jiejie Liu³ , Kaichao Feng³ , Miao Jing^1,2 , Xurui Wang^1,2 , Yun-Cai Liu⁴ , Qian Mei^3,* , Weidong Han^3,* , Zhengfan Jiang^1,2,*

¹Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing 100871, China
²Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China
³Department of Bio-therapeutic, the First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
⁴Institute for Immunology, Peking-Tsinghua Center for Life Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
⁵Present address: Jill Roberts Institute for Research in Inflammatory Bowel Disease (JRI), Weill Cornell Medicine, Cornell University, New York, NY, USA
⁶Present address: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
These authors contributed equally: Mengze Lv, Meixia Chen Correspondence: Qian Mei(meiqnn@hotmail.com)Weidong Han(hanwdrsw69@yahoo.com)Zhengfan Jiang(jiangzf@pku.edu.cn)

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, Mn2+ 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 Mn2+ 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 Mn2+ 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.

https://doi.org/10.1038/s41422-020-00395-4

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