Manganese is critical for antitumor immune responses via cGAS-STING and improves the efficacy of clinical immunotherapy.
Manganese is critical for antitumor immune responses via cGAS-STING and improves the efficacy of clinical immunotherapy.
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DOI：
10.1038/s41422-020-00395-4
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发表时间：
2020-11
期刊：
影响因子：
44.1
通讯作者：
Jiang Z
中科院分区：
文献类型：
--
作者：
Lv M;Chen M;Zhang R;Zhang W;Wang C;Zhang Y;Wei X;Guan Y;Liu J;Feng K;Jing M;Wang X;Liu YC;Mei Q;Han W;Jiang Z
CD8+T细胞介导的肿瘤清除通常受到PD-1和PD-L1等抑制性分子相互作用的抑制，这种相互作用在正常情况下起到刹车的作用，防止T细胞过度反应，但被肿瘤细胞利用来逃避免疫监视。免疫检查点抑制剂通过消除这种刹车，使癌症治疗方法发生了革命性的变化。不幸的是，只有少数癌症患者对免疫疗法有反应，这可能是由于免疫力不足。抗肿瘤免疫依赖于cGAS-STING通路的激活，因为STING缺陷小鼠无法刺激肿瘤浸润性树突状细胞(DC)激活CD8+T细胞。STING激动剂还可以增强自然杀伤(NK)细胞，以介导CD8+T细胞耐药肿瘤的清除。因此，刺痛激动剂受到了广泛的追捧。我们先前发现，通过激活cGAS-STING，锰对于宿主防御胞质dsDNA是不可或缺的。在这里，我们报告说，锰在肿瘤的先天免疫感应和增强针对肿瘤的获得性免疫反应中也是必不可少的。锰缺乏小鼠显著促进肿瘤生长和转移，肿瘤浸润性CD8+T细胞显著减少。机制上，Mn2+可促进DC和巨噬细胞成熟，促进肿瘤特异性抗原提呈，促进CD8+T细胞分化、活化和NK细胞活化，增强记忆性CD8+T细胞。将Mn2+与免疫检查点抑制相结合，协同提高了抗肿瘤效果，并减少了小鼠所需的抗PD-1抗体剂量。重要的是，用Mn2+和抗PD-1抗体联合方案完成的一期临床试验显示出良好的疗效，在大多数晚期转移性实体瘤患者中表现出I型干扰素的诱导、可控的安全性和对免疫治疗的恢复反应。我们认为，这种联合策略值得进一步的临床翻译。
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.
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DOI：
10.1084/jem.20101159
发表时间：
2011-09-26
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Fuertes MB;Kacha AK;Kline J;Woo SR;Kranz DM;Murphy KM;Gajewski TF
通讯作者：
Gajewski TF
DOI：
10.1073/pnas.1512832112
发表时间：
2015-12-15
影响因子：
11.1
作者：
Demaria, Olivier;De Gassart, Aude;Gilliet, Michel
通讯作者：
Gilliet, Michel
影响因子：
30.5
作者：
Dunn, GP;Bruce, AT;Schreiber, RD
通讯作者：
Schreiber, RD
PD-1检查点途径的分子和生化方面。
DOI：
10.1056/nejmra1514296
发表时间：
2016-11-03
期刊：
The New England journal of medicine
影响因子：
--
作者：
Boussiotis VA
通讯作者：
Boussiotis VA
DOI：
10.1084/jem.20101158
发表时间：
2011-09-26
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Diamond MS;Kinder M;Matsushita H;Mashayekhi M;Dunn GP;Archambault JM;Lee H;Arthur CD;White JM;Kalinke U;Murphy KM;Schreiber RD
通讯作者：
Schreiber RD