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.
Highlights
Cervical cancer is caused by a persistent infection with high-risk human papillomavirus (HPV) types, and is an immunogenic disease which requires a highly immunosuppressive microenvironment in order to progress and metastasize [1]
Www.impactjournals.com/oncotarget myeloid cells in all pelvic lymph nodes from five squamous cell carcinoma (SCC) cervical cancer patients with lymph node metastases
Our results point to a strong immunosuppressive microenvironment in LN+ from patients with cervical cancer with high Treg levels, low CD8+ T cell/Treg ratio, and high levels of PD-L1+- and HLA-DR+ myeloid cells, which is consistent with previous data based from flowcytometric analyses [7, 9] and immunohistochemical stainings [2]
Summary
Cervical cancer is caused by a persistent infection with high-risk human papillomavirus (HPV) types, and is an immunogenic disease which requires a highly immunosuppressive microenvironment in order to progress and metastasize [1]. In line with the excess of suppressive immune cell subsets, decreased levels of interferon-γ (IFNγ) and high levels of interleukin-6 (IL-6), IL-10, and vascular endothelial growth factor (VEGF) were detected in cervical metastatic lymph nodes [7, 9]. This immune suppression in metastatically involved lymph nodes will stand in the way of effective anti-tumor immunity and may have to be tackled before immunotherapy can be effective and halt metastatic spread. While systemic immune checkpoint blockade in cervical cancer is currently being explored in several clinical trials [11], more localized targeting of the microenvironment of cervical tumors and their TDLN may be even more effective while minimizing side effects [12]
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