Roles of estrogens on myeloid-derived suppressor cells in cancer and autoimmune diseases
Roles of estrogens on myeloid-derived suppressor cells in cancer and autoimmune diseases
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DOI：
10.1038/cmi.2017.129
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发表时间：
2017-12
影响因子：
24.1
通讯作者：
Jing Ren;Yayi Hou;Tingting Wang
中科院分区：
文献类型：
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作者：
Jing Ren;Yayi Hou;Tingting Wang
雌激素作为一种类固醇激素，在多种生理、病理功能和肿瘤发生中的作用已被广泛研究。我们先前证明雌激素通过ADAM17促进MICA/B的分泌，从而帮助肺癌细胞逃避NKG2D介导的免疫监视。1雌激素受体α(ERα)和ERβ是两种高亲和力的雌激素核受体，通过激活多种生长因子和抑制抑癌基因而促进肿瘤的发生。2以ER为靶点的抗雌激素治疗已成功地用于治疗ER阳性乳腺癌。雌激素受体拮抗剂作为乳腺癌和卵巢癌的一种有效治疗手段已被临床广泛接受。3然而，对于一些卵巢癌患者来说，抗雌激素治疗并不合适。大多数研究仅集中在ER通路上，而忽略了雌激素与肿瘤微环境中其他免疫细胞之间的相互作用。髓系来源的抑制细胞(MDSCs)构成了一组来自髓系的异质性免疫细胞。MDSCs最初被描述为T细胞，特别是CD8+T细胞的抑制者，并已被证实在癌症和自身免疫性疾病等疾病中发挥关键作用。关于雌激素与MDSCs的关系，已有研究表明，雌激素可通过ERα信号动员MDSCs并增强其抑制功能，从而促进不同雌激素不敏感肿瘤的发生发展，这种作用不依赖于雌激素对肿瘤细胞的直接作用。4雌激素信号通过增强Janus激活的激酶2和SRC的活性，激活骨髓髓系前体细胞中的信号转导和转录因子3途径，导致荷瘤小鼠骨髓单核细胞和粒细胞MDSCs的数量增加。一项类似的研究表明，雌激素通过在肿瘤微环境中积累MDSCs来促进ER阴性乳腺癌的进展。5雌激素对抗肿瘤免疫和促肿瘤炎症的显著作用不依赖于对肿瘤细胞的直接作用，这为抗雌激素药物的临床应用提供了新的视角。因此，特异性阻断ERα的ER拮抗剂可用于ER阳性乳腺癌和其他恶性肿瘤的辅助治疗。多药耐药干细胞在免疫治疗过程中的诱导导致许多肿瘤的治疗失败。抗雌激素药物在减轻免疫治疗耐药方面的有效性需要进一步证实。此外，MDSCs还被报道在多种癌症的病例中促进肿瘤血管生成、侵袭和转移。抗雌激素药物对肿瘤转移和血管生成的影响亟待进一步研究。大量研究表明，雌激素与炎症和自身免疫性疾病(如系统性红斑狼疮(SLE))的患病率存在强烈的性别差异，男女比例为10：1。雌激素在SLE中起着重要作用，并与代谢变化和芳香化酶基因多态性有关。6骨髓间充质干细胞在系统性红斑狼疮进展中的作用鲜有报道，目前仍不确定。我们先前证明，在狼疮小鼠和高疾病活动性的SLE患者中，脾粒细胞MDSCs和单核细胞MDSCs均显著扩增。MDSCs通过调节辅助性T细胞(Th17)和调节性T细胞之间的平衡，在SLE的发病机制中起着至关重要的作用。7确定雌激素是否参与…是很重要的
As a steroid hormone, estrogen has been extensively investigated in various physiological and pathological functions and in carcinogenesis. We previously demonstrated that estrogen promotes the secretion of MICA/B through ADAM17, which helps lung cancer cells evade NKG2D-mediated immune surveillance. 1 Estrogen receptor α (ERα) and ERβ are two high-affinity nuclear receptors of estrogen that promote cancer by activating multiple growth factors and inhibiting tumorsuppressor genes. 2 Anti-estrogen therapy targeting the ER has been successfully used to treat ER-positive breast cancers. ER antagonists have been widely accepted in clinical practice as an effective treatment for breast tumors and a subset of ovarian cancers. 3 However, for some ovarian cancer patients, anti-estrogen therapy is not suitable. Most studies have exclusively focused on ER pathways and have ignored the interaction between estrogens and other immune cells in the tumor microenvironment. Myeloid-derived suppressor cells (MDSCs) constitute a heterogeneous group of immune cells from the myeloid lineage. MDSCs were originally described as suppressors of T cells, particularly CD8+ T cells and have been confirmed to have critical roles in diseases, such as cancers and autoimmune disorders. Regarding the relationship between estrogen and MDSCs, it has been demonstrated that estrogens can promote the development of different estrogen-insensitive tumors by mobilizing MDSCs and enhancing their inhibitory functions via ERα signaling, which is independent of the direct effects of estrogens on tumor cells. 4 Estrogen signaling activates the signal transducer and activator of transcription factor 3 pathway in bone marrow myeloid precursors by enhancing Janus-activated kinase 2 and SRC activity, resulting in increased numbers of both myelomonocytic MDSCs and granulocytic MDSCs in tumor-bearing mice. A similar study showed that estrogens promote the progression of ER-negative breast cancer through the accumulation of MDSCs in the tumor microenvironment. 5 The significant effects of estrogens on antitumor immunity and tumor-promoting inflammation independent of direct actions on tumor cells provide novel insight into the clinical use of anti-estrogen drugs. Accordingly, ER antagonists that specifically block ERα could be used as adjuvant therapy in ER-positive breast cancer and other malignancies. MDSC induction during immunotherapy contributes to treatment failure in many tumors. The efficiency of anti-estrogen drugs in mitigating immunotherapeutic resistance requires further confirmation. In addition, MDSCs are reported to promote tumor angiogenesis, invasion and metastasis in cases of multiple cancers. Further studies are urgently needed to clarify the effects of anti-estrogen agents on tumor metastasis and angiogenesis.Extensive studies have shown that estrogens are strongly implicated in gender differences in the prevalence of inflammatory and autoimmune diseases such as systemic lupus erythematosus (SLE), which shows a male-to-female ratio of 10: 1. Estrogens have an important role in SLE and are related to metabolic changes and aromatase gene polymorphisms. 6 The role of MDSCs in SLE progression is rarely reported and remains uncertain. We previously demonstrated that both splenic granulocytic MDSCs and monocytic MDSCs are significantly expanded in mice with lupus and in high-disease-activity SLE patients. MDSCs have a crucial role in the pathogenesis of SLE by regulating the balance between T helper type 17 (Th17) and regulatory T cells. 7 It is important to determine whether estrogens are involved in the …