Immune suppressive activity of myeloid-derived suppressor cells in cancer requires inactivation of the type I interferon pathway.
Immune suppressive activity of myeloid-derived suppressor cells in cancer requires inactivation of the type I interferon pathway.
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DOI：
10.1038/s41467-021-22033-2
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发表时间：
2021-03-19
影响因子：
16.6
通讯作者：
Gabrilovich DI
中科院分区：
文献类型：
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作者：
Alicea-Torres K;Sanseviero E;Gui J;Chen J;Veglia F;Yu Q;Donthireddy L;Kossenkov A;Lin C;Fu S;Mulligan C;Nam B;Masters G;Denstman F;Bennett J;Hockstein N;Rynda-Apple A;Nefedova Y;Fuchs SY;Gabrilovich DI
髓源性抑制细胞（MDSC）是病理活化的中性粒细胞和单核细胞，具有强大的免疫抑制活性。这些细胞在加速肿瘤进展和破坏抗癌疗法的功效方面起着重要作用。限制MDSC活性的自然机制还不清楚。在这里，我们提出的证据表明，I型干扰素（IFN1）受体信号作为一个通用的机制，限制收购这些细胞的抑制活性。在来自癌症患者和小鼠肿瘤模型的MDSC中发现该受体的IFNAR1链的下调。IFNAR1的减少依赖于p38蛋白激酶的激活，并且是免疫抑制表型激活所需的。尽管IFNAR1的缺失不足以将嗜中性粒细胞和单核细胞转化为MDSC，但IFNAR1在荷瘤小鼠中的遗传稳定破坏了MDSC的抑制活性并具有有效的抗肿瘤作用。使用p38的抑制剂与干扰素诱导疗法组合稳定IFNAR1产生稳健的抗肿瘤作用。因此，MDSC功能的负调节机制可以在治疗上被利用。I型干扰素信号传导在髓源性抑制细胞（MDSC）活性控制中的作用仍存在争议。在这里，作者表明，在癌症患者和荷瘤小鼠的MDSC中观察到I型干扰素受体的下调，并且是激活其免疫抑制特性所必需的。
Myeloid-derived suppressor cells (MDSC) are pathologically activated neutrophils and monocytes with potent immune suppressive activity. These cells play an important role in accelerating tumor progression and undermining the efficacy of anti-cancer therapies. The natural mechanisms limiting MDSC activity are not well understood. Here, we present evidence that type I interferons (IFN1) receptor signaling serves as a universal mechanism that restricts acquisition of suppressive activity by these cells. Downregulation of the IFNAR1 chain of this receptor is found in MDSC from cancer patients and mouse tumor models. The decrease in IFNAR1 depends on the activation of the p38 protein kinase and is required for activation of the immune suppressive phenotype. Whereas deletion of IFNAR1 is not sufficient to convert neutrophils and monocytes to MDSC, genetic stabilization of IFNAR1 in tumor bearing mice undermines suppressive activity of MDSC and has potent antitumor effect. Stabilizing IFNAR1 using inhibitor of p38 combined with the interferon induction therapy elicits a robust anti-tumor effect. Thus, negative regulatory mechanisms of MDSC function can be exploited therapeutically. The role of type I interferon signalling in the control of myeloid derived suppressor cells (MDSC) activity remains controversial. Here the authors show that downregulation of type I interferon receptor is observed in MDSC from cancer patients and tumor-bearing mice and is required for the activation of their immune suppressive properties.
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影响因子：
--
作者：
Chen MF;Kuan FC;Yen TC;Lu MS;Lin PY;Chung YH;Chen WC;Lee KD
通讯作者：
Lee KD
影响因子：
50.3
作者：
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通讯作者：
Goldszmid RS
影响因子：
11.1
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Bhattacharya, Sabyasachi;Katlinski, Kanstantsin V.;Reichert, Maximilian;Takano, Shigetsugu;Brice, Angela;Zhao, Bin;Yu, Qiujing;Zheng, Hui;Carbone, Christopher J.;Katlinskaya, Yuliya V.;Leu, N. Adrian;McCorkell, Kelly A.;Srinivasan, Satish;Girondo, Melanie;Rui, Hallgeir;May, Michael J.;Avadhani, Narayan G.;Rustgi, Anil K.;Fuchs, Serge Y.
通讯作者：
Fuchs, Serge Y.
影响因子：
17.1
作者：
Highfill SL;Cui Y;Giles AJ;Smith JP;Zhang H;Morse E;Kaplan RN;Mackall CL
通讯作者：
Mackall CL
影响因子：
10.1
作者：
Hossain, Fokhrul;Al-Khami, Amir A.;Ochoa, Augusto C.
通讯作者：
Ochoa, Augusto C.