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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...

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Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Singapore 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785004/
https://www.ncbi.nlm.nih.gov/pubmed/32839553
http://dx.doi.org/10.1038/s41422-020-00395-4
Descripción
Sumario: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.