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

Adam Rainczuk, Jyothsna R. Rao, Jessica L. Gathercole, Nicole J. Fairweather, Simon Chu, Rina Masadah, Thomas W. Jobling, Santanu Deb-Choudhury, Jolon Dyer, Andrew N. Stephens

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Patients with high-grade, serous epithelial ovarian carcinoma (HGSOC) are generally diagnosed with extensive peritoneal metastases, and exhibit 5-year survival rates +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.

Original languageEnglish
Pages (from-to)530-541
Number of pages12
JournalInternational Journal of Cancer
Volume134
Issue number3
DOIs
Publication statusPublished - 2014

Keywords

  • CXCL10
  • dipeptidyl peptidase
  • leucocyte
  • mass spectrometry
  • ovarian cancer

Cite this

Rainczuk, Adam ; Rao, Jyothsna R. ; Gathercole, Jessica L. ; Fairweather, Nicole J. ; Chu, Simon ; Masadah, Rina ; Jobling, Thomas W. ; Deb-Choudhury, Santanu ; Dyer, Jolon ; Stephens, Andrew N. / Evidence for the antagonistic form of CXC-motif chemokine CXCL10 in serous epithelial ovarian tumours. In: International Journal of Cancer. 2014 ; Vol. 134, No. 3. pp. 530-541.
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title = "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 +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.",
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year = "2014",
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Rainczuk, A, Rao, JR, Gathercole, JL, Fairweather, NJ, Chu, S, Masadah, R, Jobling, TW, Deb-Choudhury, S, Dyer, J & Stephens, AN 2014, 'Evidence for the antagonistic form of CXC-motif chemokine CXCL10 in serous epithelial ovarian tumours' International Journal of Cancer, vol. 134, no. 3, pp. 530-541. https://doi.org/10.1002/ijc.28393

Evidence for the antagonistic form of CXC-motif chemokine CXCL10 in serous epithelial ovarian tumours. / Rainczuk, Adam; Rao, Jyothsna R.; Gathercole, Jessica L.; Fairweather, Nicole J.; Chu, Simon; Masadah, Rina; Jobling, Thomas W.; Deb-Choudhury, Santanu; Dyer, Jolon; Stephens, Andrew N.

In: International Journal of Cancer, Vol. 134, No. 3, 2014, p. 530-541.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Rainczuk, Adam

AU - Rao, Jyothsna R.

AU - Gathercole, Jessica L.

AU - Fairweather, Nicole J.

AU - Chu, Simon

AU - Masadah, Rina

AU - Jobling, Thomas W.

AU - Deb-Choudhury, Santanu

AU - Dyer, Jolon

AU - Stephens, Andrew N.

PY - 2014

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N2 - Patients with high-grade, serous epithelial ovarian carcinoma (HGSOC) are generally diagnosed with extensive peritoneal metastases, and exhibit 5-year survival rates +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.

AB - Patients with high-grade, serous epithelial ovarian carcinoma (HGSOC) are generally diagnosed with extensive peritoneal metastases, and exhibit 5-year survival rates +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.

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