Nuclear Aurora kinase A triggers programmed death-ligand 1-mediated immune suppression by activating MYC transcription in triple-negative breast cancer.
Nuclear Aurora kinase A triggers programmed death-ligand 1-mediated immune suppression by activating MYC transcription in triple-negative breast cancer.
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核极光激酶 A 通过激活三阴性乳腺癌中的 MYC 转录来触发程序性死亡配体 1 介导的免疫抑制
DOI：
10.1002/cac2.12190
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发表时间：
2021-09
期刊：
影响因子：
--
通讯作者：
Piao H
中科院分区：
文献类型：
--
作者：
Sun S;Zhou W;Li X;Peng F;Yan M;Zhan Y;An F;Li X;Liu Y;Liu Q;Piao H
越来越多的研究报道癌基因调节免疫系统的组成部分，这表明这是肿瘤发生的一种机制。极光激酶A（Aurora kinase A，AURKA）是一种丝氨酸/苏氨酸激酶，参与细胞有丝分裂，对肿瘤细胞增殖、转移和耐药性至关重要。然而，AURKA参与免疫应答调节的机制尚不清楚。因此，本研究旨在研究AURKA在三阴性乳腺癌（TNBC）免疫调节中的作用。将外周血单核细胞（PBMC）与TNBC细胞共培养。使用xCELLigence真实的-Time Cell Analyzer-MP系统检测免疫细胞对TNBC细胞的杀伤效率。通过定量真实的-时间聚合酶链反应（qRT-PCR）检测免疫效应分子的表达，以评价免疫功能。此外，为了验证体内AURKA调节的免疫应答，将具有AURKA过表达或下调的4 T1鼠乳腺癌细胞系移植到BALB/c小鼠中。免疫组化和流式细胞术进一步评价免疫细胞在肿瘤中的分布和比例。TNBC细胞中AURKA的下调通过激活CD 8 + T细胞增殖和活性来增加免疫应答。细胞核而不是细胞质AURKA衍生的程序性死亡配体1（PD-L1）表达与其激酶活性无关。机制研究表明，核AURKA通过MYC依赖性途径增加PD-L1表达。PD-L1过表达主要逆转AURKA沉默诱导的免疫效应分子表达，包括白细胞介素-（IL-2）、干扰素-γ（IFN-γ）和穿孔素。此外，在4 T1移植的BALB/c小鼠模型中，AURKA表达与肿瘤浸润性CD 8 + T细胞的富集和活性呈负相关。核AURKA通过MYC依赖性途径升高PD-L1表达，并有助于TNBC的免疫逃避。靶向核AURKA的治疗可以恢复针对肿瘤的免疫反应。本研究表明，核AURKA而不是其激酶活性通过MYC依赖性途径诱导PD-L1表达。此外，AURKA的下调导致体内CD 8 + T细胞浸润和活化增加。因此，我们的数据为AURKA参与三阴性乳腺癌的免疫逃避提供了证据。
Increasing studies have reported that oncogenes regulate components of the immune system, suggesting that this is a mechanism for tumorigenesis. Aurora kinase A (AURKA), a serine/threonine kinase, is involved in cell mitosis and is essential for tumor cell proliferation, metastasis, and drug resistance. However, the mechanism by which AURKA is involved in immune response regulation is unclear. Therefore, this study aimed to investigate the role of AURKA in immune regulation in triple‐negative breast cancer (TNBC). Peripheral blood mononuclear cells (PBMCs) were co‐cultured with TNBC cells. The xCELLigence Real‐Time Cell Analyzer‐MP system was used to detect the killing efficiency of immune cells on TNBC cells. The expression of immune effector molecules was tested by quantitative real‐time polymerase chain reaction (qRT‐PCR) to evaluate immune function. Furthermore, to validate AURKA‐regulated immune response in vivo, 4T1 murine breast cancer cell line with AURKA overexpression or downregulation was engrafted into BALB/c mice. The distribution and proportion of immune cells in tumors were further evaluated by immunohistochemistry and flow cytometry. Downregulation of AURKA in TNBC cells increased immune response by activating CD8+ T cell proliferation and activity. Nuclear rather than cytoplasmic AURKA‐derived programmed death‐ligand 1 (PD‐L1) expression was independent of its kinase activity. Mechanistic investigations showed that nuclear AURKA increased PD‐L1 expression via an MYC‐dependent pathway. PD‐L1 overexpression mostly reversed AURKA silencing‐induced expression of immune effector molecules, including interleukin‐ (IL‐2), interferon‐γ (IFN‐γ), and perforin. Moreover, AURKA expression was negatively correlated with the enrichment and activity of tumor‐infiltrating CD8+ T cells in 4T1 engrafted BALB/c mouse model. Nuclear AURKA elevated PD‐L1 expression via an MYC‐dependent pathway and contributed to immune evasion in TNBC. Therapies targeting nuclear AURKA may restore immune responses against tumors. The present study showed that nuclear AURKA rather than its kinase activity induced PD‐L1 expression via a MYC‐dependent pathway. In addition, downregulation of AURKA led to increased CD8+ T cell infiltration and activation in vivo. Thus, our data provided evidences for the involvement of AURKA in immune evasion of triple‐negative breast cancer.
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DOI：
10.1126/science.aac9935
发表时间：
2016-04-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Casey SC;Tong L;Li Y;Do R;Walz S;Fitzgerald KN;Gouw AM;Baylot V;Gütgemann I;Eilers M;Felsher DW
通讯作者：
Felsher DW
影响因子：
45.3
作者：
Adams, Sylvia;Gray, Robert J.;Badve, Sunil S.
通讯作者：
Badve, Sunil S.
影响因子：
4.7
作者：
Lassus, Heini;Staff, Synnove;Butzow, Ralf
通讯作者：
Butzow, Ralf
影响因子：
11.5
作者：
Lee, Jong Woo;Parameswaran, Janaki;Burtness, Barbara
通讯作者：
Burtness, Barbara
有丝分裂激酶 Aurora-A 通过激活 Cofilin-F-actin 途径诱导乳腺细胞迁移和乳腺癌转移
影响因子：
11.2
作者：
Wang, Li-hui;Xiang, Jin;Liu, Quentin
通讯作者：
Liu, Quentin