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415 Single-cell map of the dynamic changes underlying platinum-based chemotherapy with or without bevacizumab in high-grade serous tubo-ovarian carcinoma
  1. S Olbrecht1,2,3,
  2. P Busschaert2,
  3. L Loverix1,2,3,
  4. A Vandestichele1,
  5. T Laga1,2,3,
  6. T Van Gorp1,2,
  7. E Van Nieuwenhuysen1,2,
  8. S Han1,2,
  9. T Baert1,2,
  10. AS Van Rompuy4,5,
  11. D Lambrechts3,6 and
  12. I Vergote1,2
  1. 1University Hospitals Leuven, Department of Gynaecology and Obstetrics, Leuven, Belgium
  2. 2Catholic University of Leuven, Department of Gynaecologic Oncology, Leuven, Belgium
  3. 3VIB – Center for Cancer Biology, Leuven, Belgium
  4. 4Catholic University of Leuven, Department of Translational Cell and Tissue Research, Leuven, Belgium
  5. 5University Hospitals Leuven, Department of Imaging and pathology, Leuven, Belgium
  6. 6Catholic University of Leuven, Department of Translational Genetics, Leuven, Belgium


Introduction/Background*The vascular endothelial growth factor (VEGF) plays an import role in emergence and spread of high-grade serous tubo-ovarian carcinoma (HGSTOC). Bevacizumab, a monoclonal antibody targeting VEGFA, has therefore been added to first-line treatment of advanced HGSTOC. We here map the dynamics of different stromal components of the tumour microenvironment under chemotherapy with or without bevacizumab.

Methodology We performed single-cell RNA-sequencing on 62,461 cells sampled from 6 HGSTOC patients before and after neo-adjuvant platin-based chemotherapy with or without bevacizumab. We identified 44 stromal cell subclusters on which we applied Mixed-effects modelling of Associations of Single Cells to identify cell populations associated with bevacizumab exposure and pathological response using the chemotherapeutic response score.

Result(s)*Our study revealed diverse stromal cell subsets associated with bevacizumab exposure. The addition of bevacizumab to frontline chemotherapy increased the odds of endothelial cell (ECs) prevalence by a 3-fold (OR 2.91, 95%CI:2.36-3.58; p<0.001) in comparison to 13-fold when treated with only chemotherapy (OR 13.42, 95%CI:11.29-15.52; p<0.001). Especially for tip cells, essential for vessel sprouting, a negative odds ratio was found for its association with bevacizumab exposure (OR 0.32, 95%CI:0.21-0.50; p<0.001) while chemotherapy only increased the odds of tip cell recruitment (OR 2.67, 95%CI:1.87-3.80; p<0.001). Tip cell receptors KDR, FLT1 and co-receptor NRP1 were significantly downregulated after bevacizumab exposure. In addition, ECs treated with bevacizumab showed lower scores for hypoxia signatures and demonstrated a significant downregulation of hypoxia-induced genes, including HIF1α. Furthermore, bevacizumab was associated with decreased number of regulatory T cells (OR 0.40, 95%CI:0.32-0.51; p<0.001). Interestingly, the addition of bevacizumab was associated with increased influx of tumour-associated macrophages (TAMs). Especially, PDGFC-expressing TAMs were strongly associated with bevacizumab exposure (OR 21.33, 95%CI:9.01-50.46; p<0.001) and poor response (OR 49.06, 95%CI:18.46-130.39 p<0.001). These cells express platelet-derived growth factor-C (PDGFC) and NRP1 providing a possible escape mechanism to activate KDR in absence of VEGFA.

Conclusion*We here provide initial evidence on the mechanisms underlying early response to bevacizumab and frontline chemotherapy in HGSTOC, including tip cell impairment, reduced hypoxia and a decrease in regulatory T cells. However, bevacizumab exposure increased the influx of PDGFC-expressing macrophages capable to bypass VEGFA-dependent angiogenesis.

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