Annexin A2/TLR2/MYD88 pathway induces arginase 1 expression in tumor-associated neutrophils.
Annexin A2/TLR2/MYD88 pathway induces arginase 1 expression in tumor-associated neutrophils.
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DOI：
10.1172/jci153643
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发表时间：
2022-11-15
影响因子：
15.9
通讯作者：
Houghton, A. McGarry
中科院分区：
文献类型：
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作者：
Zhang, Huajia;Zhu, Xiaodong;Friesen, Travis J.;Kwak, Jeff W.;Pisarenko, Tatyana;Mekvanich, Surapat;Velasco, Mark A.;Randolph, Timothy W.;Kargl, Julia;Houghton, A. McGarry
髓系细胞通过精氨酸消耗经由精氨酸酶1（ARG 1）抑制T细胞活力。尽管许多研究探索了ARG 1干扰淋巴细胞功能的机制，但对其产生和释放的细胞群体仍然知之甚少。在这里，我们发现，中性粒细胞谱系细胞，而不是单核细胞或巨噬细胞在人类非小细胞肺癌（NSCLC）中表达ARG 1。重要的是，我们发现大约40%的肿瘤相关中性粒细胞（TAN）活跃地转录ARG 1 mRNA。为了确定在TAN中诱导ARG 1 mRNA的机制，我们利用FPLC和MS/MS筛选能够诱导中性粒细胞中ARG 1 mRNA表达的肿瘤源性因子。这些研究确定ANXA 2是TAN中ARG 1 mRNA表达的主要驱动因素。从机制上讲，ANXA 2通过中性粒细胞中的TLR 2/MYD 88轴发出信号，以诱导ARG 1 mRNA表达。目前的研究描述了我们认为是ARG 1 mRNA表达在癌症中性粒细胞中调节的一种新机制，并强调了中性粒细胞谱系细胞在抑制肿瘤浸润淋巴细胞中的核心作用。
Myeloid lineage cells suppress T cell viability through arginine depletion via arginase 1 (ARG1). Despite numerous studies exploring the mechanisms by which ARG1 perturbs lymphocyte function, the cellular populations responsible for its generation and release remain poorly understood. Here, we showed that neutrophil lineage cells and not monocytes or macrophages expressed ARG1 in human non–small cell lung cancer (NSCLC). Importantly, we showed that approximately 40% of tumor-associated neutrophils (TANs) actively transcribed ARG1 mRNA. To determine the mechanism by which ARG1 mRNA is induced in TANs, we utilized FPLC followed by MS/MS to screen tumor-derived factors capable of inducing ARG1 mRNA expression in neutrophils. These studies identified ANXA2 as the major driver of ARG1 mRNA expression in TANs. Mechanistically, ANXA2 signaled through the TLR2/MYD88 axis in neutrophils to induce ARG1 mRNA expression. The current study describes what we believe to be a novel mechanism by which ARG1 mRNA expression is regulated in neutrophils in cancer and highlights the central role that neutrophil lineage cells play in the suppression of tumor-infiltrating lymphocytes.