Histone deacetylase 6 regulates the immunosuppressive properties of cancer-associated fibroblasts in breast cancer through the STAT3-COX2-dependent pathway
Histone deacetylase 6 regulates the immunosuppressive properties of cancer-associated fibroblasts in breast cancer through the STAT3-COX2-dependent pathway
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DOI：
10.1038/s41388-018-0379-9
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发表时间：
2018-11-08
期刊：
影响因子：
8
通讯作者：
Kang, Jiuhong
中科院分区：
文献类型：
--
作者：
Li, Ang;Chen, Ping;Kang, Jiuhong
癌相关成纤维细胞是乳腺肿瘤的重要组成部分，对肿瘤的进展和转移至关重要。然而，表观遗传修饰在乳腺肿瘤中驱动cas功能中的作用尚不清楚。在此，我们报道了组蛋白去乙酰化酶6 (HDAC6)， II类组蛋白去乙酰化酶之一，在乳腺肿瘤的cas中经常上调，并促进免疫抑制微环境。在cas中，HDAC6的遗传或药理学破坏会延缓肿瘤生长，抑制髓源性抑制细胞和调节性T细胞的肿瘤募集，改变巨噬细胞表型开关，并增加体内CD8+和CD4+ T细胞的活化。在机制上，我们发现前列腺素E2/环氧化酶-2 （COX2）是通过调节STAT3激活的hdac - 6在CAFs中的主要靶点。在hdac6敲低的cas中过表达COX2可以完全恢复成纤维细胞的免疫抑制特性。临床观察到HDAC6、p-STAT3、COX2在人乳腺癌组织中间质表达水平呈正相关。高间质表达的HDAC6与较差的生存预后显著相关。总之，我们的研究结果表明，成纤维细胞HDAC6是一个重要的表观遗传介质，参与编程免疫抑制肿瘤微环境，抑制抗肿瘤免疫。因此，HDAC6可能是改善乳腺癌免疫治疗的良好潜在靶点。
Cancer-associated fibroblasts (CAFs) are important components in breast tumors and essential for tumor progression and metastasis. However, the role of epigenetic modification in driving the function of CAFs within breast tumors is only marginally known. Herein, we reported that histone deacetylase 6 (HDAC6), one of class II histone deacetylases, was frequently upregulated in the CAFs of breast tumor and promotes an immunosuppressive microenvironment. The genetic or pharmacologic disruption of HDAC6 in CAFs delays tumor growth, inhibits the tumor recruitment of myeloid-derived suppressor cells and regulatory T cells, alters the macrophage phenotype switch, and increases the CD8+ and CD4+ T-cell activation in vivo. Mechanistically, we identified prostaglandin E2/cyclooxygenase-2 (COX2) as a major target of HDAC6 in CAFs by regulating STAT3 activation. Overexpressing COX2 in HDAC6-knockdown CAFs can completely restore the immunosuppressive properties of the fibroblasts. Clinically, a positive correlation among the stromal expression levels of HDAC6, p-STAT3, and COX2 in human breast cancer was observed. High-stromal expression of HDAC6 was markedly associated with poor survival outcome. Overall, our findings indicated that fibroblastic HDAC6 was a vital epigenetic mediator involved in programming an immunosuppressive tumor microenvironment that dampens antitumor immunity. Thus, HDAC6 may be a good potential target to improve breast cancer immunotherapy.