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Foxp3+ cell infiltration and granzyme B+/Foxp3+ cell ratio are associated with outcome in neoadjuvant chemotherapy-treated ovarian carcinoma

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Abstract

Preoperative neoadjuvant chemotherapy (NAC) can significantly reduce tumour burden in patients with primarily unresectable chemosensitive tumours, allowing a more complete cytoreduction during debulking surgery and facilitating evaluation of tumour chemosensitivity, identification of appropriate treatment options and improvement of intervention protocols. In this study, we investigate, using immunohistochemistry, the impact of platinum/taxane-based NAC (NAC) on tumour-infiltrating lymphocytes (TILs) in advanced epithelial ovarian cancer (EOC) and their relationship with clinical outcome. All patients had clinical response, as shown by ascites volume and CA125 levels compared to pre-treatment findings. NAC intervention significantly increased CD4+, CD8+ and granzyme B+ infiltration while Foxp3+ accumulation remained unaffected. TILs were prognostically neutral for both progression-free survival (PFS) and overall survival (OS) before NAC. In contrast, after NAC, elevated granzyme B+ infiltration displayed a tendency for improved PFS (log-rank 0.064). Further, low Foxp3+ cell density was associated with longer PFS, as compared with strong Foxp3+ infiltration (median 20.94 vs. 11.24 months; log-rank 0.0001) and with improved OS (median 30.75 vs. 16.04 months, respectively; log-rank 0.056), demonstrating clear prognostic significance for PFS. In addition, high granzyme B+/Foxp3+ ratio post-NAC strongly correlated with improved PFS compared to low granzyme B+/Foxp3+ cell ratio (median 17.88 vs. 11.24 months, respectively), and showed to be a favourable prognostic factor for PFS (log-rank 0.014). Our findings indicate that NAC elicited an immunologic profile in which low immunosuppressive Foxp3+ infiltration and elevated numbers of activated granzyme B+ cells were significantly associated with EOC-specific PFS, suggesting a contribution of immunologic effects to improved clinical outcome.

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Acknowledgments

This is a single institution analysis of clinical data collected within a multicenter phase 2 trial, PRIMOVAR, ClinicalTrials.gov Identifier: NCT00551577, sponsored by Sanofi-Aventis Deutschland GmbH. We thank Christiane Esch for technical assistance with immunohistochemistry.

Conflict of interest statement

Walther Kuhn (principal investigator) received research funding from Sanofi-Aventis. All other authors indicated no potential conflict of interest.

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Author notes

  1. Nicolaus Friedrichs

    Present address: Zentrale Klinische Forschung, Freiburg University, Freiburg, Germany

Authors and Affiliations

  1. Department of Gynaecology and Obstetrics, Centre for Integrated Oncology Bonn, Bonn University Medical Centre, Sigmund Freud-Str. 25, 53105, Bonn, Germany

    Martin Pölcher, Michael Braun, Christian Rudlowski, Eva Bercht, Axel Sauerwald, Mignon-Denise Keyver-Paik, Kirsten Kübler, Walther C. Kuhn & Juan-José Hernando

  2. Institute of Pathology, Centre for Integrated Oncology Bonn, Bonn University Medical Centre, Bonn, Germany

    Nicolaus Friedrichs & Reinhard Büttner

  3. Institute for Medical Biometry, Informatics, and Epidemiology, Bonn University Medical Centre, Bonn, Germany

    Rolf Fimmers

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  1. Martin Pölcher
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Correspondence to Martin Pölcher.

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M. Pölcher and M. Braun contributed equally to this work.

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Pölcher, M., Braun, M., Friedrichs, N. et al. Foxp3+ cell infiltration and granzyme B+/Foxp3+ cell ratio are associated with outcome in neoadjuvant chemotherapy-treated ovarian carcinoma. Cancer Immunol Immunother 59, 909–919 (2010). https://doi.org/10.1007/s00262-010-0817-1

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