期刊
BRITISH JOURNAL OF CANCER
卷 115, 期 5, 页码 553-563出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/bjc.2016.172
关键词
CXCL9; CXCL10; ovarian cancer; cyclooxygenase; tumour-infiltrating lymphocytes
类别
资金
- Clinical and Translational Science Collaborative of Cleveland
- National Center for Advancing Translational Sciences component of the National Institutes of Health [KL2TR000440]
- Deutsche Forschungsgemeinschaft [BR 4733/1-1]
- NIH roadmap for Medical Research
Background: Tumour-infiltrating lymphocytes (TILs) are associated with improved survival in several epithelial cancers. The two chemokines CXCL9 and CXCL10 facilitate chemotactic recruitment of TILs, and their intratumoral accumulation is a conceivable way to improve TIL-dependent immune intervention in cancer. However, the prognostic impact of CXCL9 and CXCL10 in high-grade serous ovarian cancer (HGSC) is largely unknown. Methods: One hundred and eighty four cases of HGSC were immunohistochemically analyzed for CXCL9, CXCL10. TILs were assessed using CD3, CD56 and FOXP3 staining. Chemokine regulation was investigated using the ovarian cancer cell lines OV-MZ-6 and SKOV-3. Results: High expression of CXCL9 and CXCL10 was associated with an approximately doubled overall survival (n = 70, CXCL9: HR 0.41; P = 0.006; CXCL10: HR 0.46; P = 0.010) which was confirmed in an independent validation set (n = 114; CXCL9: HR 0.60; P = 0.019; CXCL10: HR 0.52; P = 0.005). Expression of CXCR3 ligands significantly correlated with TILs. In human ovarian cancer cell lines the cyclooxygenase (COX) metabolite Prostaglandin E2 was identified as negative regulator of chemokine secretion, whereas COX inhibition by indomethacin significantly upregulated CXCL9 and CXCL10. In contrast, celecoxib, the only COX inhibitor prospectively evaluated for therapy of ovarian cancer, suppressed NF-kappa B activation and inhibited chemokine release. Conclusion: Our results support the notion that CXCL9 and CXCL10 exert tumour-suppressive function by TIL recruitment in human ovarian cancer. COX inhibition by indomethacin, not by celecoxib, may be a promising approach to concomitantly improve immunotherapies.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据