Mapping Epitopes Recognised by Autoantibodies Shows Potential for the Diagnosis of High-Grade Serous Ovarian Cancer and Monitoring Response to Therapy for This Malignancy

Abstract

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.

Heat Shock Factor 1 Inhibition: A Novel Anti-Cancer Strategy with Promise for Precision Oncology

“…In addition, HSF1 can be employed as a therapy response parameter. Continuing from the previous work [46], the role of IgA in detecting HSI-PO4 contributes to an understanding of treatment response in HGSOC. After a course of combination platinumand taxol-based treatment (carboplatin and paclitaxel), IgA levels in response to HSF1-PO4 increased considerably, establishing HSF1-PO4 as a possible tumor-associated antigen [47].…”

“…IgA, one of the AAbs employed in the above-cited study, yielded promising outcomes. The levels of anti-HSF1 IgA were higher in the early stages of HGSOC than in the advanced stages [46].…”

“…The pivotal role of HSF1 in drug resistance can be demonstrated in the binding of HSF1 to the HSE of MDR1. Transfection of active HSF1 increases MDR1 mRNA and protein levels, stimulating drug efflux and the development of drug resistance [39,46]. On the contrary, HSF1 depletion downregulates the transcription of the MDR1 gene in the cells [88].…”