A distinct pre-existing inflammatory tumour microenvironment is associated with chemotherapy resistance in high-grade serous epithelial ovarian cancer

Journal article

Background

Chemotherapy resistance is a major determinant of poor overall survival rates in high-grade serous ovarian cancer (HGSC). We have previously shown that gene expression alterations affecting the NF-κB pathway characterise chemotherapy resistance in HGSC, suggesting that the regulation of an immune response may be associated with this phenotype.

Methods

Given that intrinsic drug resistance pre-exists and is governed by both tumour and host factors, the current study was performed to examine the cross-talk between tumour inflammatory microenvironment and cancer cells, and their roles in mediating differential chemotherapy response in HGSC patients. Expression profiling of a panel of 184 inflammation-related genes was performed in 15 chemoresistant and 19 chemosensitive HGSC tumours using the NanoString nCounter platform.

Results

A total of 11 significantly differentially expressed genes were found to distinguish the two groups. As STAT1 was the most significantly differentially expressed gene (P=0.003), we validated the expression of STAT1 protein by immunohistochemistry using an independent cohort of 183 (52 resistant and 131 sensitive) HGSC cases on a primary tumour tissue microarray. Relative expression levels were subjected to Kaplan-Meier survival analysis and Cox proportional hazard regression models.

Conclusions

This study confirms that higher STAT1 expression is significantly associated with increased progression-free survival and that this protein together with other mediators of tumour-host microenvironment can be applied as a novel response predictive biomarker in HGSC. Furthermore, an overall underactive immune microenvironment suggests that the pre-existing state of the tumour immune microenvironment could determine response to chemotherapy in HGSC.

Authors: Koti, M; Siu, A; Clément, I; Bidarimath, M; Turashvili, G

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Springer Nature [academic journals on nature.com]
• Journal: British Journal of Cancer
• Volume: 112
• Issue: 7
• Pages: 1215-1222
• Publication date: 2015-03-12
• DOI: 10.1038/bjc.2015.81
• EISSN: 1532-1827
• ISSN: 0007-0920
• Language: English
• Keywords: Immunology; Gene signature; Serous fluid; Immune system; Tissue microarray; Internal medicine; Gene expression profiling; Ovarian cancer; Chemotherapy; Biology; Gene expression; Cancer research; Cancer; Tumor microenvironment; Medicine; Immunohistochemistry; Gene; Microarray analysis techniques; Pathology