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 over-express mRNA encoding the T-cell-recruiting chemokine CXCL10. Whilst tumour infiltrating CD4+/CD8+ T-cells are generally associated with good prognosis, patients diagnosed with HGSOC typically exhibit poor survival. Recently an “antagonistic” CXCL10 variant - modified by the enzyme Dipeptidyl Peptidase 4 (DPP4) - was identified as an in vivo inhibitor of leukocyte recruitment (J. Clin. Invest. 121, pp.308-317). We hypothesized that some HGSOC's might also express antagonistic CXCL10, interfering with leukocyte recruitment and contributing to poor patient prognosis.
We analyzed the expression, localization and association of CXCL10 with CD3+ T-cells in HGSOC tissues grouped according to pathology, grade and FIGO stage at diagnosis. CXCL10 was increased in a subset of HGSOC samples, and correlated with CD3+ tumour infiltrating T-cells in benign disease but not in malignancy. Immunoprecipitation and de novo sequence analysis of CXCL10 from patient samples identified the N-terminally cleaved, “antagonistic” variant in malignant tumours only. Furthermore, the cleaved variant was localized to the tumour epithelium by Imaging Mass Spectrometry. The presence of cleaved CXCL10 in tumour epithelium also correlated well with the presence of DPP4.
Our data demonstrate that antagonistic CXCL10, known to inhibit (rather than promote) leukocyte recruitment, is present in serous ovarian tumours and is associated with decreased leukocyte infiltration. We suggest that represents a previously unrecognized mechanism by which tumours might partially attenuate the early anti-tumour immune response, and is a plausible explanation for the commonly poor prognosis experienced by these patients. This finding provides new insight into ovarian tumour progression, and may lead to novel therapeutic interventions.