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

Abstract

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.

Increased STAT1 Expression in High Grade Serous Ovarian Cancer Is Associated With a Better Outcome

“…7 The preexisting inflammatory tumor microenvironment has recently been shown to be associated with the innate response to chemotherapy in several types of cancer, including ovarian HGSC. 8 The existence of the extracellular matrix closely associated with the tumor may influence the drug response phenotype, and this strengthens the idea that the tumor microenvironment may have an immunomodulatory effect on tumor behavior. 9,10 Therefore, biomarkers that inform on the immune microenvironment are good candidates for evaluation when searching for new ways of predicting the therapeutic response.…”

“…8 This study showed that a distinct STAT1-dependent tumor inflammatory microenvironment was associated with chemotherapy response in ovarian HGSC.…”

“…29 These biological differences between sensitive and resistant tumors strongly suggest that differential expression of genes and pathways related to chemotherapy response must occur. 8 Treatment with immunomodulators have been widely studied based on the tumor immunosurveillance theory, and several antineoplastic therapies have been proposed. 30 There are an increasing number of new clinical trials in ovarian cancer involving checkpoint inhibitors, adoptive T cell transfer, oncolytic viruses, and adjuvant immunotherapies.…”

Lurbinectedin Specifically Triggers the Degradation of Phosphorylated RNA Polymerase II and the Formation of DNA Breaks in Cancer Cells

“…In this regard, it was recently reported that, in combination with doxorubicin, lurbinectedin has compelling activity as a second-line treatment in patients with SCLC (43), a tumor type that could be most sensitive to transcription-targeting drugs (3-5, 7, 44, 45). Lurbinectedin has also showed impressive activity in platinum-resistant ovarian cancer (46), a subtype of ovarian cancer that has been related to gene expression alterations affecting different oncogenic pathways related to drug resistance and tumor microenvironment (47)(48)(49). Targeting transcription addiction with lurbinectedin might be similarly beneficial in the treatment of other tumor types that are known to be dependent on transcription dysregulation (50,51).…”

Tumor Microenvironment and Models of Ovarian Cancer

“…16,17 At this symposium, they present data that in chemosensitive tumors, there is upregulation of STAT1 and a type-I interferon pathway gene signature. Tumor cells with this gene signature may more effectively recruit CD8+ T-cells, resulting in a greater immunologic response and improved cancer cell treatment.…”