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

被引：78

作者：

Li, Binghao ^{[1
,2
,3
,4
]}

Wang, Zhan ^{[1
,2
]}

Wu, Hao ^{[5
]}

Xue, Mingfeng ^{[1
,6
]}

Lin, Peng ^{[1
,2
]}

Wang, Shengdong ^{[1
,2
]}

Lin, Nong ^{[1
]}

Huang, Xin ^{[1
]}

Pan, Weibo ^{[1
]}

Liu, Meng ^{[1
]}

Yan, Xiaobo ^{[1
]}

Qu, Hao ^{[1
]}

Sun, Lingling ^{[1
]}

Li, Hengyuan ^{[1
]}

Wu, Yan ^{[1
,2
]}

Teng, Wangsiyuan ^{[1
,2
]}

Wang, Zenan ^{[1
,2
]}

Zhou, Xingzhi ^{[1
,2
]}

Chen, Huabiao ^{[3
,4
]}

Poznansky, Mark C. ^{[3
,4
]}

Ye, Zhaoming ^{[1
,2
]}

机构：

[1] Zhejiang Univ, Sch Med, Affiliated Hosp 2, Musculoskeletal Tumor Ctr,Dept Orthoped, Hangzhou 310009, Zhejiang, Peoples R China

[2] Zhejiang Univ, Inst Orthoped Res, Hangzhou, Zhejiang, Peoples R China

[3] Massachusetts Gen Hosp, Dept Med, Vaccine & Immunotherapy Ctr, Charlestown, MA USA

[4] Harvard Med Sch, Charlestown, MA USA

[5] Zhejiang Canc Hosp, Dept Bone & Soft Tumor Surg, Hangzhou, Zhejiang, Peoples R China

[6] Second Hosp Jiaxing, Dept Orthoped, Jiaxing, Peoples R China

来源：

CANCER RESEARCH | 2018年 / 78卷 / 14期

基金：

中国国家自然科学基金;

关键词：

OPEN-LABEL; CHEMOKINE RECEPTOR; PROSTATE-CANCER; T-CELLS; DECITABINE; EXPRESSION; CHEMOTHERAPY; MULTICENTER; INVOLVEMENT; METASTASIS;

D O I：

10.1158/0008-5472.CAN-17-3801

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 thorn 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. (C) 2018 AACR.

引用

页码：3938 / 3953

页数：16