Combining TNFR2-Expressing Tregs and IL-6 as Superior Diagnostic Biomarkers for High-Grade Serous Ovarian Cancer Masses

Nirmala Chandralega Kampan; Apriliana Ellya Ratna Kartikasari; Cyril Deceneux; Mutsa Tatenda Madondo; Orla M McNally; Katie Louise Flanagan; Norhaslinda A Aziz; Andrew N Stephens; John Reynolds; Michael A Quinn; Magdalena Plebanski

doi:10.3390/cancers15030667

Combining TNFR2-Expressing Tregs and IL-6 as Superior Diagnostic Biomarkers for High-Grade Serous Ovarian Cancer Masses

Cancers (Basel). 2023 Jan 21;15(3):667. doi: 10.3390/cancers15030667.

Authors

Nirmala Chandralega Kampan^{1

2

3}, Apriliana Ellya Ratna Kartikasari⁴, Cyril Deceneux⁴, Mutsa Tatenda Madondo¹, Orla M McNally^{2

5}, Katie Louise Flanagan^{4

6

7}, Norhaslinda A Aziz³, Andrew N Stephens^{8

9

10}, John Reynolds¹¹, Michael A Quinn², Magdalena Plebanski^{1

4}

Affiliations

¹ Department of Immunology & Pathology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Level 6, The Alfred, Commercial Road, Melbourne, VIC 3181, Australia.
² Oncology Unit, Royal Women's Hospital, 20 Flemington Road, Parkville, VIC 3052, Australia.
³ Department of Obstetrics and Gynaecology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia.
⁴ School of Health and Biomedical Sciences, RMIT University, Melbourne, VIC 3083, Australia.
⁵ Department of Obstetrics and Gynaecology, Melbourne University, Parkville, VIC 3052, Australia.
⁶ Tasmanian Vaccine Trial Centre, Clifford Craig Foundation, Launceston General Hospital, Launceston, TAS 7250, Australia.
⁷ School of Health Sciences and School of Medicine, University of Tasmania, Hobart, TAS 7005, Australia.
⁸ Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia.
⁹ Department of Molecular and Translational Sciences, Monash University, Clayton, VIC 3800, Australia.
¹⁰ Epworth Research Institute, Epworth Healthcare, Richmond, VIC 3121, Australia.
¹¹ Biostatistics Consulting Platform, Faculty of Medicine, Nursing and Health Sciences, Monash University, Level 6, The Alfred, Commercial Road, Melbourne, VIC 3181, Australia.

Abstract

We hypothesised that the inclusion of immunosuppressive and inflammatory biomarkers in HGSOC patients would improve the sensitivity and specificity of the preoperative marker prediction of malignancy in patients with ovarian masses. We tested a panel of 29 soluble immune factors by multiplex bead immunoassay and 16 phenotypic T cell markers by flow cytometry in pre-treatment blood samples from 66 patients undergoing surgery for suspected ovarian cancer or ovarian cancer risk reduction. The potential diagnostic utility of all parameters was explored using Volcano plots, principal component analysis (PCA) and receiver operator characteristic (ROC) analysis. We also assessed the effect of culturing PBMCs from 20 healthy donors in the presence of malignant ascites fluid. The combination of TNFR2⁺ Tregs and IL-6 in the pre-treatment blood of patients with advanced HGSOC effectively discriminated patients with benign or malignant ovarian masses. In vitro culturing of the PBMCs of healthy donors in malignant ascites promoted an increase in TNFR2-expressing Tregs, which were decreased following blockade with IL-6 or STAT3 activity. Pre-treatment serum IL-6 and peripheral blood TNFR2⁺ Tregs may be potential clinical biomarkers that can discriminate patients with malignant compared to benign ovarian cancer masses, and the relationship between IL-6 and TNFR2⁺ Treg is likely to be mediated via the STAT3 signalling pathway.

Keywords: epithelial ovarian cancer; high-grade serous ovarian cancer; inflammatory soluble biomarkers; interleukin 6; platinum resistance; progression-free survival; regulatory T cells; tumour necrosis factor 2 receptor.

Grants and funding

The work was partly supported by visionary donations from John Brunner, the Women’s Cancer Fund and Ovarian Cancer Research Foundation Inc., Australia. The authors: Nirmala Kampan is supported by FRGS/1/2018/SKK08/UKM/02/6 and Australian Monash International Postgraduate Research Scholarship. Andrew Stephens is supported by a grant from the Ovarian Cancer Research Foundation of Australia (www.ORCF.com.au, accessed on 9 December 2022) and Magdalena Plebanski is a Senior NHMRC Fellow.