Lu, Zou, and Li et al. inhibited lung metastases and extended survival after tumor resection using low-dose adjuvant epigenetic therapy (AET) in several mouse models. Post-surgery and before metastasis detection, myeloid-derived suppressor cells (MDSCs) accumulated in lungs of untreated but not AET-treated mice. Cell transfer experiments indicated that the reduction in monocytic MDSCs in the pre-metastatic niche impacted survival. Mechanistically, AET reduced MDSC expression of CCR2 and migratory gene sets, and increased macrophage-associated signatures and surface markers. Combining AET with a CCR2 antagonist further extended survival.
Contributed by Alex Najibi
ABSTRACT: Cancer recurrence after surgery remains an unresolved clinical problem(1-3). Myeloid cells derived from bone marrow contribute to the formation of the premetastatic microenvironment, which is required for disseminating tumour cells to engraft distant sites(4-6). There are currently no effective interventions that prevent the formation of the premetastatic microenvironment(6,7). 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.
Author Info: (1) Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Transl
Author Info: (1) Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China. Department of Oncology, The Johns Hopkins School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. (2) Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China. (3) Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China. (4) Department of Oncology, The Johns Hopkins School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. (5) Department of Oncology, The Johns Hopkins School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. (6) Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. (7) Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China. (8) Department of Oncology, The Johns Hopkins School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. (9) Department of Oncology, The Johns Hopkins School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. (10) Department of Oncology, The Johns Hopkins School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. (11) Department of Oncology, The Johns Hopkins School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. (12) Department of Oncology, The Johns Hopkins School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. (13) Department of Oncology, The Johns Hopkins School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Air Force Medical University, Xi'an, China. (14) Department of Oncology, The Johns Hopkins School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. (15) Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. (16) Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. (17) Department of Oncology, The Johns Hopkins School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. (18) Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (19) Department of Oncology, The Johns Hopkins School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. (20) Department of Oncology, The Johns Hopkins School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. (21) Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China. (22) Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China. (23) Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Thoracic Surgery, The Seventh Medical Center of PLA General Hospital, Beijing, China. (24) Department of Oncology, The Johns Hopkins School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. (25) Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Surgery, University of Illinois College of Medicine, Chicago, IL, USA. (26) Department of Oncology, The Johns Hopkins School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. (27) Division of Medical Oncology, McMaster University, Juravinski Cancer Centre, Hamilton, Ontario, Canada. (28) Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. (29) Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. (30) Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. (31) Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. (32) Department of Surgery, Anne Arundel Medical Center, Annapolis, MD, USA. (33) Department of Oncology, The Johns Hopkins School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. (34) Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (35) Division of Hematology-Oncology, Medical University of South Carolina, Charleston, SC, USA. (36) Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, The Johns Hopkins School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. (37) Department of Otolaryngology-Head and Neck Surgery, Vanderbilt University, Nashville, TN, USA. (38) Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, Baltimore, MD, USA. School of Biomedical Engineering, Dalian University of Technology, Dalian, China. (39) Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, Baltimore, MD, USA. (40) Department of Oncology, The Johns Hopkins School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (41) Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. (42) Department of Oncology, The Johns Hopkins School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. (43) Department of Oncology, The Johns Hopkins School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. (44) Department of Oncology, The Johns Hopkins School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (45) Department of Oncology, The Johns Hopkins School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. fhousse1@jhmi.edu. Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. fhousse1@jhmi.edu. (46) Department of Oncology, The Johns Hopkins School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. sbaylin@jhmi.edu. (47) Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China. shenlin@bjmu.edu.cn. (48) Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. mabrock@jhmi.edu. Department of Oncology, The Johns Hopkins School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. mabrock@jhmi.edu.
