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Activated regulatory and memory T-cells accumulate in malignant ascites from ovarian carcinoma patients

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Abstract

Invasive ovarian cancer is associated with poor outcome. The presence of infiltrating regulatory T-cells (Tregs) suppresses protective anti-tumor immune responses, and their accumulation into the tumor microenvironment correlates with reduced survival in ovarian cancer patients. Here, we conducted a detailed characterization of CD4+ T-cells, CD8+ T-cells and Treg subsets in the peripheral blood and malignant ascites fluid from seventeen patients with ovarian carcinoma of epithelial origin. Cell distribution, activation status and proliferation status were assessed by multi-color flow cytometry. In ascites fluid, a significant accumulation of CD8+ cytotoxic T-cells and Tregs was observed compared to peripheral blood. Furthermore, a skewing toward the CD45RA− effector/memory compartment was observed in all T-cell subsets in the ascites fluid, but was most pronounced in the Treg population. Regulatory T-cells in the malignant ascites were more activated and had a higher proliferation rate compared to blood-derived cells from the same patient, and their number in ascites was positively correlated with the number of epithelial cells in effusion. In summary, we demonstrate an accumulation of activated CD4+, CD8+ and regulatory T-cells in the cancer microenvironment of ovarian carcinoma.

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Abbreviations

CCL17:

Chemokine (C–C motif) ligand 17

CCL22:

Chemokine (C–C motive) ligand 22

CCR4:

Chemokine (C–C motive) receptor 4

CTLA4:

Cytotoxic T-lymphocyte-associated protein 4

EpCAM:

Epithelial cell adhesion molecule

FIGO:

International Federation of Gynaecology and Obstetrics

FoxP3:

Forkhead box P3

IDO:

Indoleamine 2,3-dioxygenase

Ki-67:

Marker of proliferation Ki-67

MHC:

Major histocompatibility complex

PBMC:

Peripheral blood mononuclear cells

PBS:

Phosphate buffered saline

PD1:

Programmed cell death 1

TALs:

Tumor-associated lymphocytes

TILs:

Tumor-infiltrating lymphocytes

Treg:

Regulatory T-cell

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Acknowledgments

We thank the pathologists from the Department of Pathology, The Gade Institute, Haukeland University Hospital, Bergen, Norway for routine histopathological diagnosis of the tumor specimens. Furthermore, we thank Isabelle Cornez, Kristoffer W. Brudvik and Simer J. Bains for help with processing samples for subsequent analysis. This work was supported by the Research Council of Norway, the Norwegian Cancer Society, the Kristian Gerhard Jebsen Foundation and Anders Jahre’s Foundation.

Conflict of interest

The authors declare no conflict of interest.

Author information

Author notes

  1. Knut Martin Torgersen

    Present address: Oncology Business Unit, Pfizer AS, Oslo, Norway

Authors and Affiliations

  1. Biotechnology Centre of Oslo, University of Oslo, Oslo, Norway

    Johannes Landskron, Knut Martin Torgersen, Einar Martin Aandahl & Kjetil Taskén

  2. Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, P.O. Box 1137, Blindern, 0318, Oslo, Norway

    Johannes Landskron, Einar Martin Aandahl & Kjetil Taskén

  3. K. G. Jebsen Centre for Cancer Immunotherapy, University of Oslo and University Hospital of Oslo, Oslo, Norway

    Johannes Landskron & Kjetil Taskén

  4. K. G. Jebsen Inflammation Research Centre, University of Oslo and University Hospital of Oslo, Oslo, Norway

    Einar Martin Aandahl & Kjetil Taskén

  5. Section for Transplantation Surgery and Clinic for Specialized Medicine and Surgery, Oslo University Hospital Rikshospitalet, Oslo, Norway

    Einar Martin Aandahl

  6. Department of Infectious Diseases Clinic for Medicine, Oslo University Hospital, Oslo, Norway

    Kjetil Taskén

  7. Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway

    Øystein Helland & Line Bjørge

  8. Institute of Clinical Medicine, Institute of Internal Medicine, University of Bergen, Bergen, Norway

    Øystein Helland & Line Bjørge

  9. Centre of Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, 5021, Bergen, Norway

    Bjørn Tore Gjertsen

  10. Department of Internal Medicine, Hematology Section, Haukeland University Hospital, 5021, Bergen, Norway

    Bjørn Tore Gjertsen

Authors
  1. Johannes Landskron
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  2. Øystein Helland
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Correspondence to Kjetil Taskén.

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Landskron, J., Helland, Ø., Torgersen, K.M. et al. Activated regulatory and memory T-cells accumulate in malignant ascites from ovarian carcinoma patients. Cancer Immunol Immunother 64, 337–347 (2015). https://doi.org/10.1007/s00262-014-1636-6

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  • DOI: https://doi.org/10.1007/s00262-014-1636-6

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