Identification of an Unfavorable Immune Signature in Advanced Lung Tumors from Nrf2-Deficient Mice
Identification of an Unfavorable Immune Signature in Advanced Lung Tumors from Nrf2-Deficient Mice
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Nrf2缺陷小鼠晚期肺肿瘤中不利免疫特征的鉴定
DOI：
10.1089/ars.2017.7201
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发表时间：
2018-04-16
影响因子：
6.6
通讯作者：
Liby, Karen T.
中科院分区：
文献类型：
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作者：
Zhang, Di;Rennhack, Jonathan;Liby, Karen T.
目的：激活正常细胞中的核因子（红细胞衍生2）样2 （Nrf2）通路可抑制癌变，而癌细胞中的Nrf2组成型激活可促进肿瘤生长和化疗耐药。然而，在肺癌发生过程中，Nrf2激活在免疫细胞中的作用尚不明确，可能促进或抑制癌症的生长。我们的研究旨在评估Nrf2敲除（KO）小鼠与氨基甲酸乙酯刺激的野生型（WT）小鼠肺部的肿瘤负荷和免疫细胞群。结果：Nrf2 KO小鼠比WT小鼠更早出现肺肿瘤，随着时间的推移，甚至在晚期也表现出更多更大的肿瘤。与WT小鼠相比，Nrf2 KO小鼠肺中的T细胞数量较低，而肺和脾中的促肿瘤巨噬细胞和髓源性抑制细胞分别升高。此外，Nrf2 KO小鼠肿瘤中34个免疫应答基因显著上调，尤其是促进肿瘤生长的一系列细胞因子（Cxcl1、Csf1、Ccl9、Cxcl12等）和主要组织相容性复合体抗原。创新：我们的研究发现了一种新的免疫特征，其特征是肿瘤促进免疫细胞的浸润，细胞因子的升高，以及Nrf2 KO小鼠肺部和肿瘤中免疫反应基因的表达增加。在肺癌患者中也发现了一个互补的特征，支持了我们研究结果的临床意义。结论：总的来说，我们的研究结果证实了Nrf2在晚期癌变中的保护作用，并且出乎意料地表明，激活免疫细胞中的Nrf2可能有利于预防或治疗肺癌。Antioxid。氧化还原信号：00000 - 00000。
Aims: Activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway in normal cells inhibits carcinogenesis, whereas constitutive activation of Nrf2 in cancer cells promotes tumor growth and chemoresistance. However, the effects of Nrf2 activation in immune cells during lung carcinogenesis are poorly defined and could either promote or inhibit cancer growth. Our studies were designed to evaluate tumor burden and identify immune cell populations in the lungs of Nrf2 knockout (KO) versus wild-type (WT) mice challenged with vinyl carbamate.Results: Nrf2 KO mice developed lung tumors earlier than the WT mice and exhibited more and larger tumors over time, even at late stages. T cell populations were lower in the lungs of Nrf2 KO mice, whereas tumor-promoting macrophages and myeloid-derived suppressor cells were elevated in the lungs and spleen, respectively, of Nrf2 KO mice relative to WT mice. Moreover, 34 immune response genes were significantly upregulated in tumors from Nrf2 KO mice, especially a series of cytokines (Cxcl1, Csf1, Ccl9, Cxcl12, etc.) and major histocompatibility complex antigens that promote tumor growth.Innovation: Our studies discovered a novel immune signature, characterized by the infiltration of tumor-promoting immune cells, elevated cytokines, and increased expression of immune response genes in the lungs and tumors of Nrf2 KO mice. A complementary profile was also found in lung cancer patients, supporting the clinical significance of our findings.Conclusion: Overall, our results confirmed a protective role for Nrf2 in late-stage carcinogenesis and, unexpectedly, suggest that activation of Nrf2 in immune cells may be advantageous for preventing or treating lung cancer. Antioxid. Redox Signal. 00, 000-000.