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Programmed death ligand-1 over-expression correlates with malignancy and contributes to immune regulation in ovarian cancer

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Abstract

The programmed death-1 (PD-1) pathway is important in the maintenance of peripheral tolerance and homeostasis through suppression of T cell receptor signaling. As such, it is employed by many tumors as a means of immune escape. We have investigated the role of this pathway in human ovarian cancer (OC) to assess its potential role as a diagnostic and/or prognostic marker and therapeutic target, following recent clinical trial success of antibody therapy directed at this pathway. We show programmed death ligand-1 (PD-L1) expression on monocytes in the ascites and blood of patients with malignant OC is strikingly higher than those with benign/borderline disease, with no overlap in the values between these groups. We characterize the regulation of this molecule and show a role of IL-10 present in ascitic fluid. Flow cytometric analysis of T cells present in the ascites and blood showed a correlation of PD-1 expression with malignant tumors versus benign/borderline, in a similar manner to PD-L1 expression on monocytes. Finally, we demonstrate functional links between PD-L1 expression on monocytes and OC tumor cells with suppression of T cell responses. Overall, we present data based on samples obtained from women with ovarian cancer, suggesting the PD-1 pathway may be used as a reliable diagnostic marker in OC, as well as a viable target for use with PD-1/PD-L1-directed antibody immunotherapy.

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Acknowledgments

We wish to thank the clinical staff at Queen Charlotte’s hospital to their contribution to patient recruitment. Sadaf Ghaem-Maghami received funding from Rosie Williams Charitable Trust and Mann-Hodgson Trust for this work. Nor Haslinda Abdul Aziz was supported by a studentship from Malaysian Ministry of Education. Christian J. Maine was supported by an MRC studentship. Claudia Hayford was supported by Ovarian Cancer Action. Support was also provided by the Experimental Cancer Medicine Centre at Imperial College London and by the National Institute for Health Research (NIHR) Biomedical Research Centre and Ovarian Cancer Action Centre based at Imperial College London.

Conflict of interest

The authors declare that they have no conflict of interest.

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Author notes

  1. Christian J. Maine

    Present address: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, USA

  2. Andrew J. T. George

    Present address: Brunel University, London, UK

Authors and Affiliations

  1. Department of Medicine, Imperial College London, London, UK

    Christian J. Maine & Andrew J. T. George

  2. Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0HS, UK

    Nor Haslinda Abdul Aziz, Jayanta Chatterjee, Claudia Hayford, Nancy Brewig, Lynsey Whilding & Sadaf Ghaem-Maghami

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  1. Christian J. Maine
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Correspondence to Sadaf Ghaem-Maghami.

Additional information

Christian J. Maine and Nor Haslinda Abdul Aziz have contributed equally to this work.

Andrew J.T. George and Sadaf Ghaem-Maghami are senior authors with equal contribution.

Nor Haslinda Abdul Aziz is currently a member of Institute for Medical Molecular Biotechnology, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh, Selangor, Malaysia.

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Maine, C.J., Aziz, N.H.A., Chatterjee, J. et al. Programmed death ligand-1 over-expression correlates with malignancy and contributes to immune regulation in ovarian cancer. Cancer Immunol Immunother 63, 215–224 (2014). https://doi.org/10.1007/s00262-013-1503-x

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  • DOI: https://doi.org/10.1007/s00262-013-1503-x

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