Epigenetic therapy inhibits metastases by disrupting premetastatic niches

癌症研究 表观遗传学 生物 肿瘤微环境 医学 髓源性抑制细胞 癌症 免疫学 抑制器 内科学 遗传学 基因 肿瘤细胞
作者
Zhihao Lü,Jianling Zou,Shuang Li,Michael J. Topper,Yong Tao,Hao Zhang,Xi Jiao,Wenbing Xie,Xiangqian Kong,Michelle Vaz,Huili Li,Yi Cai,Limin Xia,Peng Huang,Kristen Rodgers,Beverly Lee,Joanne Riemer,Chi-Ping Day,Ray-Whay Chiu Yen,Ying Cui,Yujiao Wang,Yanni Wang,Weiqiang Zhang,Hariharan Easwaran,Alicia Hulbert,KiBem Kim,Rosalyn A. Juergens,Stephen C. Yang,Richard J. Battafarano,Errol L. Bush,Stephen Broderick,Stephen M. Cattaneo,Julie R. Brahmer,Charles M. Rudin,John Wrangle,Yuping Mei,Young J. Kim,Bin Zhang,Ken Kang‐Hsin Wang,Patrick M. Forde,Joseph B. Margolick,Barry D. Nelkin,Cynthia A. Zahnow,Drew M. Pardoll,Franck Housseau,Stephen B. Baylin,Lin Shen,Malcolm V. Brock
出处
期刊:Nature [Springer Nature]
卷期号:579 (7798): 284-290 被引量:260
标识
DOI:10.1038/s41586-020-2054-x
摘要

Cancer recurrence after surgery remains an unresolved clinical problem1–3. Myeloid cells derived from bone marrow contribute to the formation of the premetastatic microenvironment, which is required for disseminating tumour cells to engraft distant sites4–6. There are currently no effective interventions that prevent the formation of the premetastatic microenvironment6,7. Here we show that, after surgical removal of primary lung, breast and oesophageal cancers, low-dose adjuvant epigenetic therapy disrupts the premetastatic microenvironment and inhibits both the formation and growth of lung metastases through its selective effect on myeloid-derived suppressor cells (MDSCs). In mouse models of pulmonary metastases, MDSCs are key factors in the formation of the premetastatic microenvironment after resection of primary tumours. Adjuvant epigenetic therapy that uses low-dose DNA methyltransferase and histone deacetylase inhibitors, 5-azacytidine and entinostat, disrupts the premetastatic niche by inhibiting the trafficking of MDSCs through the downregulation of CCR2 and CXCR2, and by promoting MDSC differentiation into a more-interstitial macrophage-like phenotype. A decreased accumulation of MDSCs in the premetastatic lung produces longer periods of disease-free survival and increased overall survival, compared with chemotherapy. Our data demonstrate that, even after removal of the primary tumour, MDSCs contribute to the development of premetastatic niches and settlement of residual tumour cells. A combination of low-dose adjuvant epigenetic modifiers that disrupts this premetastatic microenvironment and inhibits metastases may permit an adjuvant approach to cancer therapy. In mouse models of pulmonary metastasis, adjuvant epigenetic therapy targeting myeloid-derived suppressor cells disrupts the premetastatic microenvironment after resection of primary tumours and inhibits the dissemination of residual tumour cells.
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