Evidence for the antagonistic form of CXC‐motif chemokine CXCL10 in serous epithelial ovarian tumours

Abstract

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 CD41 CD8 1 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.Epithelial ovarian cancers account for between 80 and 95% of ovarian tumours diagnosed, and remain the fourth highest cause of cancer-related mortality for women with an estimated 22,000 new cases and 14,000 deaths in the United States in 2010. 1 Despite a relatively low population incidence and incremental improvements in surgery and chemotherapy, the 5-year survival rate for patients diagnosed with ovarian neoplasms has improved only marginally over time. Although traditionally classified as serous, mucinous, clear cell or endometroid based on their histological appearance, epithelial ovarian tumours are increasingly considered as different disease subtypes with characteristic molecular genetic alterations (reviewed in Ref.2). In particular, high-or low-grade serous epithelial tumours are now believed to represent distinct molecular diseases (termed Type I or Type II) with different underlying pathologies. Low-grade (Type I) tumours are believed to progress through benign and borderline stages to malignancy, typically exhibit mutations in KRAS and BRAF (amongst othe...

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