Research Papers: Immunology:

Nodal metastasis in cervical cancer occurs in clearly delineated fields of immune suppression in the pelvic lymph catchment area

A. Marijne Heeren _, Eline de Boer, Maaike C.G. Bleeker, René J.P. Musters, Marrije R. Buist, Gemma G. Kenter, Tanja D. de Gruijl and Ekaterina S. Jordanova

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Oncotarget. 2015; 6:32484-32493. https://doi.org/10.18632/oncotarget.5398

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A. Marijne Heeren1,2, Eline de Boer1, Maaike C.G. Bleeker3, René J.P. Musters4, Marrije R. Buist5, Gemma G. Kenter1,5,6, Tanja D. de Gruijl2, Ekaterina S. Jordanova1

1Center Gynecological Oncology Amsterdam (CGOA), Department of Obstetrics and Gynecology, VU University Medical Center, 1081 HV Amsterdam, The Netherlands

2Department of Medical Oncology, VU University Medical Center-Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands

3Department of Pathology, VU University Medical Center, 1081 HV Amsterdam, The Netherlands

4Laboratory for Physiology, Institute for Cardiovascular Research, VU University Medical Center, 1081 BT Amsterdam, The Netherlands

5Center Gynecological Oncology Amsterdam (CGOA), Department of Obstetrics and Gynecology, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands

6Center Gynecological Oncology Amsterdam (CGOA), Department of Gynecology, Netherlands Cancer Institute - Antoni van Leeuwenhoek, 1006 BE Amsterdam, The Netherlands

Correspondence to:

Ekaterina S. Jordanova, e-mail: [email protected]

Keywords: Immunology and Microbiology Section, Immune response, Immunity, cervical cancer, tumor-draining lymph nodes, metastatic niche, tregs, PD-L1-myeloid cells

Received: August 04, 2015     Accepted: September 16, 2015     Published: September 28, 2015


In cervical cancer, high frequencies of regulatory T cells (Tregs) and immunosuppressive PD-L1+CD14+ antigen-presenting cells dominate the microenvironment of tumor-positive lymph nodes (LN+). It is unknown whether this is restricted to LN+ or precedes metastasis, emanating from the primary tumor and spreading through tumor-draining lymph nodes (TDLNs). To investigate immunosuppression in the lymphatic basin of cervical tumors, all dissected TDLNs of five cervical cancer patients (in total 9 LN+ and 74 tumor-negative lymph nodes (LN-)) were analyzed for FoxP3+ Tregs, CD8+ T cells, HLA-DR+- and PD-L1+ myeloid cells by immunohistochemistry.

Tregs and PD-L1+ cells were found to form an immunosuppressive cordon around metastatic tumor cells. Importantly, whereas high HLA-DR+- and PD-L1+ cell rates were strongly associated with LN+, elevated Treg levels and decreased CD8+ T cell/Treg ratios were found similar in LN+ and adjacent LN-, as compared to LN- at more distant anatomical localizations. These data suggest that delineated fields of Treg-associated immune suppression in anatomically co-localized TDLNs enable metastasis by creating metastatic niches. This may be of importance for decision-making regarding (surgical) intervention in cervical cancer. Future efforts should include the implementation of immunotherapeutic regimens to overcome this immune suppression, establish loco-regional control and halt systemic tumor spread.

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