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Cancer Res. 2018 Jul 15;78(14):3938-3953. doi: 10.1158/0008-5472.CAN-17-3801. Epub 2018 May 7.

Epigenetic Regulation of CXCL12 Plays a Critical Role in Mediating Tumor Progression and the Immune Response In Osteosarcoma.

Li B1,2,3, Wang Z1,2, Wu H4, Xue M1,5, Lin P1,2, Wang S1,2, Lin N1, Huang X1, Pan W1, Liu M1, Yan X1, Qu H1, Sun L1, Li H#1, Wu Y1,2, Teng W1,2, Wang Z#1,2, Zhou X1,2, Chen H3, Poznansky MC3, Ye Z6,2.

Author information

1
Musculoskeletal Tumor Center, Department of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, P.R. China.
2
Institute of Orthopedic Research, Zhejiang University, Hangzhou, P.R. China.
3
Vaccine and Immunotherapy Center, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts.
4
Department of Bone and Soft Tumor Surgery, Zhejiang Cancer Hospital, Hangzhou, P.R. China.
5
Department of Orthopedics, The Second Hospital of Jiaxing, Jiaxing, P.R. China.
6
Musculoskeletal Tumor Center, Department of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, P.R. China. yezhaoming@zju.edu.cn.
#
Contributed equally

Abstract

The mechanism by which osteosarcomas metastasize is elusive, and challenges remain regarding its treatment with modalities including immunotherapy. CXCL12 is deeply involved in the process of tumor metastasis and T-cell homing, which is driven by a chemokine gradient, but healthy bones are supposed to preferentially express CXCL12. Here, we show for the first time that osteosarcomas epigenetically downregulate CXCL12 expression via DNA methyltransferase 1 (DNMT1) and consequently acquire the ability to metastasize and to impair cytotoxic T-cell homing to the tumor site. Analysis of human osteosarcoma cases further revealed that CXCL12 expression strongly correlated with overall survival. Evaluations on fresh human chemotherapy-free osteosarcoma samples also showed a positive correlation between CXCL12 concentration and the number of intratumoral lymphocytes. Critically, treatment targeting DNMT1 in immunocompetent mouse models significantly elevated expression of CXCL12 in tumors, resulting in a robust immune response and consequently eradicating early lung metastases in addition to suppressing subcutaneous tumor growth. These antitumor effects were abrogated by CXCL12-CXCR4 blockade or CD8+ T-cell depletion. Collectively, our data show that CXCL12 regulation plays a significant role in both tumor progression and immune response, and targeting CXCL12 is promising for therapeutics against osteosarcoma.Significance: Epigenetic regulation of CXCL12 controls metastasis and immune response in osteosarcoma, suggesting epigenetic therapies or therapies targeting CXCL12 have potential for therapeutic intervention in osteosarcoma. Cancer Res; 78(14); 3938-53. ©2018 AACR.

PMID:
29735547
DOI:
10.1158/0008-5472.CAN-17-3801
[Indexed for MEDLINE]
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