Evidence For The Antagonistic Form Of Cxc-Motif Chemokine Cxcl10 In Serous Epithelial Ovarian Tumours

Patients with high-grade, serous epithelial ovarian carcinoma (HGSOC) are generally diagnosed with extensive peritoneal metastases, and exhibit 5-year survival rates <30%. A subset of these tumours, defined as immunoreactive, overexpress mRNA encoding the T-cell-recruiting chemokine CXCL10 (10-kDa interferon gamma-induced protein; C-X-C motif chemokine 10). Tumour-infiltrating CD4(+)CD8(+) T-cells are a well-documented, positive prognostic indicator for HGSOC patients; paradoxically, however, patients diagnosed with HGSOC (overexpressing CXCL10 and therefore theorised to recruit T-cells) typically exhibit poor survival. Recently, an antagonistic CXCL10 variant was identified that inhibited leucocyte recruitment to inflamed liver in vivo (Casrouge et al., J Clin Invest 2011;121:308-17). We hypothesised that immunoreactive HGSOC might also express antagonistic CXCL10, interfering with leucocyte recruitment and contributing to poor patient prognosis. CXCL10 expression was analysed in HGSOC tissues grouped according to pathology, grade and FIGO stage at diagnosis, and its localisation and association with T-cells established by immunohistochemical staining in tissue microarrays. CXCL10 expression was increased in a subset of serous epithelial tumour samples; however, it did not correlate well with CD45-positive tumour infiltrate. Immunoprecipitation and de novo sequence analysis of CXCL10 identified the N-terminally cleaved, antagonistic variant of CXCL10 specifically in malignant tumours, and not in benign ovarian disease. The data demonstrate the presence of the antagonistic form of CXCL10 in HGSOC for the first time, and provide a partial explanation for reduced leucocyte infiltration observed in these tumours. We suggest that CXCL10 cleavage and subsequent antagonism of immune cell recruitment may be a feature of the immunoreactive HGSOC subtype, leading to early impairment of the immune response and subsequently worsening patient prognosis.What's new? The development and progression of ovarian cancer is influenced by tumor-infiltrating immune cells, particularly T-lymphocyte-recruiting chemokines. The chemokine CXCL10 may play a key role in this anti-tumor immune response, and thereby aid survival, though previous studies have been inconclusive. Here, an antagonistic form of CXCL10, recently reported to inhibit leukocyte recruitment in liver disease, was isolated from malignant, high-grade serous epithelial ovarian carcinomas (HGSOCs) but not from benign HGSOC. The presence of the antagonistic form correlated with decreased leukocyte infiltration into tumors, suggesting a novel mechanism by which tumors might attenuate the anti-tumor immune response.