Abstract
Low-dose adjuvant epigenetic therapy (AET) reduced metastasis and promoted survival in mouse models.
Major Finding: Low-dose adjuvant epigenetic therapy (AET) reduced metastasis and promoted survival in mouse models.
Mechanism: AETs downregulate CCR2 and CXCR2 to block migration of myeloid-derived suppressor cells to the lung.
Impact: Based on the mechanistic evidence, a clinical trial of AETs plus CCR2 antagonists is being initated.
Surgical resection of tumors can be curative, but many patients treated with surgery with curative intent still die of recurrent metastases. Metastasis depends on a favorable microenvironment in the premetastatic site. Based on previous clinical observations of reduced postsurgical recurrence in a small cohort of patients with early-stage non–small cell lung cancer (NSCLC) who received low-dose adjuvant epigenetic therapy (AET) and the finding that a combination of epigenetic modifiers can abrogate metastasis in an immunocompetent mouse model of aggressive NSCLC, Lu, Zou, Li, and colleagues investigated the mechanism by which AET may affect premetastatic niches. Experiments using three different syngeneic mouse models of aggressive pulmonary metastasis revealed a critical role for myeloid-derived suppressor cells (MDSC) in metastasis, with an accumulation of MDSCs in the lungs occurring prior to the development of metastasis. Low-dose adjuvant treatment with 5-azacytidine (a DNA methylation inhibitor) and entinostat (a histone deacetylase inhibitor) hindered migration of MDSCs via downregulation of CCR2 and CXCR2, leading to the hypothesis—confirmed in further experiments—that low-dose AETs may prevent accumulation of large populations of MDSCs in the lung and thus block pulmonary metastasis. Deeper investigation revealed that low-dose AET treatment promoted the adoption of an interstitial macrophage-like phenotype in MDSCs in the lung prior to metastasis. Importantly, low-dose AET treatment reduced pulmonary metastases and prolonged both disease-free survival and overall survival in mouse models. The observed reduction in metastasis was not T-cell mediated, as demonstrated by experiments in which CD4+ and CD8+ T cells were depleted. A synergistic effect on disease-free and overall survival was also noted between low-dose AET and CCR2 antagonists, in line with the previously described mode of MDSC migration to premetastatic niches in the lungs. Together, these results provide detailed mechanistic insight into the propagation of lung metastases, and the authors plan to translate these findings into a clinical trial of low-dose AET and CCR2 antagonists in early-stage cancer with the aim of preventing metastatic recurrence.
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