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

// A. Marijne Heeren 1, 2 , Eline de Boer 1 , Maaike C.G. Bleeker 3 , René J.P. Musters 4 , Marrije R. Buist 5 , Gemma G. Kenter 1, 5, 6 , Tanja D. de Gruijl 2 , Ekaterina S. Jordanova 1 1 Center Gynecological Oncology Amsterdam (CGOA), Department of Obstetrics and Gynecology, VU University Medical Center, 1081 HV Amsterdam, The Netherlands 2 Department of Medical Oncology, VU University Medical Center-Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands 3 Department of Pathology, VU University Medical Center, 1081 HV Amsterdam, The Netherlands 4 Laboratory for Physiology, Institute for Cardiovascular Research, VU University Medical Center, 1081 BT Amsterdam, The Netherlands 5 Center Gynecological Oncology Amsterdam (CGOA), Department of Obstetrics and Gynecology, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands 6 Center 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: e.jordanova@vumc.nl 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 ABSTRACT 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.