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#377 NETosis-related cytokines levels in the peritoneal fluid from advanced high-grade serous ovarian cancer patients
  1. Sarai Tomás-Pérez1,
  2. Julia Oto2,3,
  3. Aitor Cuadros-Lozano1,4,
  4. Bárbara Andrea Mc Cormack1,2,
  5. Raquel Herranz2,
  6. Eva González-Cantó1,
  7. Cristina Aghababyan1,4,
  8. María Castaño2,
  9. Isabel Alemán-Cabrera2,
  10. Susana Torres-Martínez5,6,7,
  11. Alejandro Herreros-Pomares8,
  12. Antoni Llueca9,10,11,
  13. Josep Marí-Alexandre1,12,
  14. Pilar Medina2 and
  15. Juan Gilabert-Estellés1,4,13
  1. 1Research Laboratory in Biomarkers in Reproduction, Obstetrics and Gynecology, Research Foundation of the General University Hospital of Valencia, Valencia, Spain
  2. 2Hemostasis, Thrombosis, Arteriosclerosis and Vascular Biology Research Group, Medical Research Institute Hospital La Fe, Valencia, Spain
  3. 3Deparment of Gynecology and Obstetrics, Münster University Hospital, Münster, Münster, Germany
  4. 4Department of Obstetrics and Gynecology, General University Hospital of Valencia Consortium, Valencia, Spain
  5. 5Research Laboratory in Molecular Oncology, Research Foundation of the General University Hospital of Valencia, Valencia, Spain
  6. 6Joint Unit CIPF-FIHGUV TRIAL, Valencia, Spain
  7. 7Network Biomedical Research Center (CIBERONC), Madrid, Spain
  8. 8Gynaecological Oncology Laboratory, Department of Oncology, KU Leuven, Leuven, Belgium
  9. 9Department of Obstetrics and Gynecology, General University Hospital of Castellon, Castellón, Castellón, Spain
  10. 10Multidisciplinary Unit of Abdominal Pelvic Oncology Surgery (MUAPOS), General University Hospital of Castellon, Castellon, Spain
  11. 11Department of Medicine, University Jaume I, Castellón, Spain
  12. 12Department of Pathology, General University Hospital of Valencia Consortium, Valencia, Spain
  13. 13Department of Pediatrics, Obstetrics and Gynecology, University of Valencia, Valencia, Spain


Introduction/Background High-grade serous ovarian cancer (HGSOC) is the most lethal gynecologic cancer. This tumor spreads following peritoneal fluid (PF) dynamics, being the most representative biofluid of the tumor micro-environment (TME). In the TME, neutrophils can participate in cancer progression through neutrophil extracellular traps formation (NETosis). Evidence in murine OC models suggests that the primary tumor secrete specific cytokines (G-CSF, GROα, IL-8, MCP-1), triggering neutrophil recruitment and NETosis in the peritoneal cavity. Thus, we aimed to identify whether these NETosis-related cytokines are increased in the TME of HGSOC patients and to unravel their association with NETosis biomarkers.

Methodology PF samples from advanced-HGSOC patients without neoadjuvant treatment (NT) (n=36), with NT (n=13), and control women (n=21) were analyzed. A simultaneous quantification of G-CSF, GROα, IL-1β, IL-6, IL-8, MCP-1, and TNFα was performed. Levels of NETosis biomarkers (cell-free DNA, nucleosomes, citrullinated histone 3, calprotectin, and myeloperoxidase) were quantified. R (v.3.6.2) was used for statistical analyses.

Results Compared to control women, patients without NT presented a significantly higher concentration of GROα, IL-6, IL-8 and TNFα p≤0.004 (figure 1). In NT patients, the levels of the 4 cytokines decreased to those of controls. Considering patients without NT and control women, a positive correlation was observed among the 4 cytokines (Spearman-ρ≥0.389; p≤0.011) and between the cytokines and the 5 NETosis biomarkers (Spearman-ρ≥0.361; p≤0.039).

Conclusion The observed increase of GROα, IL-6, IL-8 and TNFα levels in advanced-HGSOC patients’ PF demonstrate their presence in the HGSOC TME. Interestingly, NT decreased cytokines levels approaching to those of controls. The positive correlation described between the 4 cytokines and NETosis biomarkers suggest their possible involvement in triggering NETosis in the peritoneal cavity. Altogether, we found that GROα, IL-6, IL-8 and TNFα are present in HGSOC TME and could be involved in neutrophil recruitment and induction of NETosis, thus favoring HGSOC progression.

Abstract #377 Figure 1

NETosis-related cytokines levels in peritoneal fluid samples of control women (n=21), high-grade serous ovarian cancer patients with neoadjuvant treatment (NT) (n=13) and without NT (n=36). (A) GROa. (B) IL-6. (C) IL-8. (D) TNFa. *** p<0.001; **p<0.01; Mann-Whitney U test.

Disclosures This research was funded by the ‘Instituto de Salud Carlos III Fondo Europeo de Desarrollo Regional’ (PI20/00075, PI22/01872) and the ‘Fundación para la Investigación del Hospital General Universitario de Valencia’ (FIHGUV Awards 2021). S. T.-P. is supported by pre-doctoral a grant from the ‘Junta Asociada Provincial de Valencia de la Asociación Española Contra el Cáncer (AECC)’; J. O. is supported by post-doctoral a grant from the ‘Alexander von Humboldt Foundation’; B. A. M.-C. is supported by a post-doctoral grant from the ‘Sociedad Española de Trombosis y Hemostasia (Prime SETH), R. H. is supported by a pre-doctoral grant from the ‘Instituto de Salud Carlos III’ (FI21/00171); E. G.-C., I. A.-C. and S. T.-M are supported by pre-doctoral grants from the ‘Generalitat Valenciana’ (ACIF/2020/216, ACIF/2021/192 and ACIF/2018/275, respectively). A. H.-P. is supported by a post-doctoral Marie Sklodowska-Curie grant (No. 101064216).

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