Abstract
Simple SummaryMost women are diagnosed with high-grade serous ovarian cancer (HGSOC) at stage III, when the cancer has already spread, contributing to poor survival outcomes. However, while earlier diagnosis increases survival rates, there is a lack of early diagnosis biomarkers. Previously, autoantibodies specific for phosphorylated heat shock factor 1 (HSF1-PO4) were suggested as a potential diagnostic biomarker for early-stage HGSOC. In the present study, specific regions within HSF1 were identified, tested and confirmed as useful biomarkers, with comparable diagnostic potential to the full protein, across two separate clinical cohorts. Additionally, antibody responses to HSF1-PO4 and the corresponding peptides were found to increase following a round of standard first-line chemotherapy. Together, our data suggest that the identified short peptide sequences could be used as practical alternatives to support early diagnosis or monitor responses to chemotherapy.Autoantibodies recognising phosphorylated heat shock factor 1 (HSF1-PO4) protein are suggested as potential new diagnostic biomarkers for early-stage high-grade serous ovarian cancer (HGSOC). We predicted in silico B-cell epitopes in human and murine HSF1. Three epitope regions were synthesised as peptides. Circulating immunoglobulin A (cIgA) against the predicted peptide epitopes or HSF1-PO4 was measured using ELISA, across two small human clinical trials of HGSOC patients at diagnosis. To determine whether chemotherapy would promote changes in reactivity to either HSF1-PO4 or the HSF-1 peptide epitopes, IgA responses were further assessed in a sample of patients after a full cycle of chemotherapy. Anti-HSF1-PO4 responses correlated with antibody responses to the three selected epitope regions, regardless of phosphorylation, with substantial cross-recognition of the corresponding human and murine peptide epitope variants. Assessing reactivity to individual peptide epitopes, compared to HSF1-PO4, improved assay sensitivity. IgA responses to HSF1-PO4 further increased significantly post treatment, indicating that HSF1-PO4 is a target for immunity in response to chemotherapy. Although performed in a small cohort, these results offer potential insights into the interplay between autoimmunity and ovarian cancer and offer new peptide biomarkers for early-stage HGSOC diagnosis, to monitor responses to chemotherapy, and widely for pre-clinical HGSOC research.
Highlights
Heat shock factor 1 (HSF1) is the key regulator of the heat shock response, where it drives transcription of many target genes
As HSF1 is highly conserved [1], to explore whether cross-reactivity occurs for potential utility in ovarian cancer animal models, the orthologous murine sequences were identified using the National Center for Biotechnology Information (NCBI) protein blast, and the corresponding peptides synthesised (Figure 1)
To further compare the IgA-specific antibody responses of the peptides to that of HSF1-PO4, we explored sensitivity of the responses by titrating samples from individuals with a high, medium or low/no response towards full HSF1-PO4, and measured IgA-specific responses (Figure 5)
Summary
Heat shock factor 1 (HSF1) is the key regulator of the heat shock response, where it drives transcription of many target genes. HSF1 is associated with neurodegenerative diseases and cancers [5,6,7,8,9,10]. In clinical studies, increased HSF1 expression levels are correlated with poor prognosis and advanced metastasis in breast cancer [11,12], non-small cell lung cancer [13], gastric cancer [14], oesophageal squamous cell cancer [15], ovarian cancer [16] and others. High expression of HSF1 has been associated with cancer stem cells [16], as well as drug resistance [12]. For these reasons, HSF1 has been proposed as a potential target for therapies
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