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1382 DKK1 is a biomarker and immunotherapeutic target for bone metastases in malignant cancers
  1. Tao Shi,
  2. Kaijie Liang,
  3. Xiaoyu Zhou,
  4. Xueru Song,
  5. Hanbing Wang,
  6. Yipeng Zhang,
  7. Lixia Yu,
  8. Baorui Liu and
  9. Jia Wei
  1. The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China


Background Malignant tumors with bone metastases seriously threaten the survival of cancer patients. However, the understanding of bone-tumor microenvironment remains poor, and currently, there is no effective therapeutic target for bone metastases.

Methods Serum Dickkopf-1 (DKK1) expression from healthy donors and gastric cancer (GC) patients were detected. Mouse GC and breast cancer bone metastasis model was established by intro-caudal artery (CA) GC cell injection, and in vivo efficacy of DKK1 blockade with murine DKK1 antibody (mDKN-01) was evaluated by micro-CT, MRI and IHC staining modalities. The bone-tumor immune microenvironment (bone-TIME) was analyzed via flow cytometry and immunofluorescence.

Results Serum DKK1 expressions were increased in GC patients (n=63) than in healthy donors (n=25), and stage IV GC patients (n=42) had higher serum DKK1 levels than stage II-III patients (n=21), with bone-metastatic patients (n=22) displaying the highest DKK1 level. Also, serum DKK1 levels are increased in patients with progressive disease (PD), while decreased in patients who had complete response (CR)/partial response (PR) to treatments. DKK1 blockade by mDKN-01 obviously reduced the tumor burden of bone metastases, and significantly inhibited osteoclast activation and alleviates bone destruction in different bone metastasis models. Moreover, the bone-TIME was improved after DKK1 blockade, with increased proportions of CD8+ T cells, M1-like macrophages, and activated dendritic cells (DCs).

Conclusions Our study suggests DKK1 as a potential predictor to bone metastasis and progressive disease in cancer patients. Blockade of DKK1 brings an improved bone-TIME, therefore, DKK1 could be considered as a novel and promising immunotherapeutic target for bone metastases.

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