Identification of a subset of immunosuppressive P2RX1-negative neutrophils in pancreatic cancer liver metastasis.
Identification of a subset of immunosuppressive P2RX1-negative neutrophils in pancreatic cancer liver metastasis.
复制标题
胰腺癌肝转移中免疫抑制 P2RX1 阴性中性粒细胞亚群的鉴定
DOI：
10.1038/s41467-020-20447-y
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发表时间：
2021-01-08
影响因子：
16.6
通讯作者：
Zhang ZG
中科院分区：
文献类型：
--
作者：
Wang X;Hu LP;Qin WT;Yang Q;Chen DY;Li Q;Zhou KX;Huang PQ;Xu CJ;Li J;Yao LL;Wang YH;Tian GA;Yang JY;Yang MW;Liu DJ;Sun YW;Jiang SH;Zhang XL;Zhang ZG
肝转移性胰腺导管腺癌（PDAC）形成的免疫抑制微环境对于肿瘤细胞逃避免疫破坏至关重要。中性粒细胞是转移性肿瘤微环境的重要组成部分，并表现出异质性。然而，中性粒细胞在PDAC肝转移中的特异性表型、功能和调节机制仍不清楚。在这里，我们表明，一个子集的P2 RX 1阴性中性粒细胞积累在临床和小鼠PDAC肝转移。鼠PDAC肝转移浸润中性粒细胞的RNA测序显示，P2 RX 1缺陷型中性粒细胞表达的免疫抑制分子水平增加，包括PD-L1，并具有增强的线粒体代谢。从机制上讲，转录因子Nrf 2在P2 RX 1缺陷型中性粒细胞中上调，并与PD-L1表达和代谢重编程相关。抗PD-1中和抗体足以损害P2 RX 1缺陷型中性粒细胞对OVA活化的OT 1 CD 8 + T细胞的免疫抑制作用。因此，我们的研究揭示了转移性PDAC肿瘤通过积累免疫抑制性P2 RX 1阴性中性粒细胞亚群来逃避抗肿瘤免疫的机制。
The immunosuppressive microenvironment that is shaped by hepatic metastatic pancreatic ductal adenocarcinoma (PDAC) is essential for tumor cell evasion of immune destruction. Neutrophils are important components of the metastatic tumor microenvironment and exhibit heterogeneity. However, the specific phenotypes, functions and regulatory mechanisms of neutrophils in PDAC liver metastases remain unknown. Here, we show that a subset of P2RX1-negative neutrophils accumulate in clinical and murine PDAC liver metastases. RNA sequencing of murine PDAC liver metastasis-infiltrated neutrophils show that P2RX1-deficient neutrophils express increased levels of immunosuppressive molecules, including PD-L1, and have enhanced mitochondrial metabolism. Mechanistically, the transcription factor Nrf2 is upregulated in P2RX1-deficient neutrophils and associated with PD-L1 expression and metabolic reprogramming. An anti-PD-1 neutralizing antibody is sufficient to compromise the immunosuppressive effects of P2RX1-deficient neutrophils on OVA-activated OT1 CD8+ T cells. Therefore, our study uncovers a mechanism by which metastatic PDAC tumors evade antitumor immunity by accumulating a subset of immunosuppressive P2RX1-negative neutrophils.
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影响因子：
64.8
作者：
Finisguerra V;Di Conza G;Di Matteo M;Serneels J;Costa S;Thompson AA;Wauters E;Walmsley S;Prenen H;Granot Z;Casazza A;Mazzone M
通讯作者：
Mazzone M
影响因子：
10.1
作者：
Kulig, Paulina;Burkhard, Sara;Becher, Burkhard
通讯作者：
Becher, Burkhard
DOI：
10.1164/rccm.201102-0271oc
发表时间：
2011-10-15
影响因子：
24.7
作者：
Kong, Xiaoni;Thimmulappa, Rajesh;Biswal, Shyam
通讯作者：
Biswal, Shyam
影响因子：
15.9
作者：
Eash, Kyle J.;Greenbaum, Adam M.;Link, Daniel C.
通讯作者：
Link, Daniel C.
影响因子：
5.8
作者：
Lachmann, Alexander;Xu, Huilei;Ma'ayan, Avi
通讯作者：
Ma'ayan, Avi