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

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.

Regulatory roles of miRNA-758 and matrix extracellular phosphoglycoprotein in cervical cancer

“…Lymph node metastasis is the most common type of remote metastasis and is closely associated with poor prognosis. Identifying this metastasis can help to judge prognosis and treatment strategies ( 20 ). Deep understanding of lymph node metastasis and lymphangiogenesis in cervical cancer is helpful to identify novel and effective treatment methods.…”

T- and NK-cell populations with regulatory phenotype and markers of apoptosis in circulating lymphocytes of patients with CIN3 or microcarcinoma of the cervix: evidence for potential mechanisms of immune suppression

“…Given that in experimental settings CD8 + T cells were shown to convert to suppressor CD8 Tregs under the influence of the tumor cell microenvironment [ 35 , 37 ], it can be assumed that expansion of CD8 Tregs observed in systemic circulation of cervical cancer patients at a pre-metastatic stage might reflect important local level changes in their quantities, that provide a foothold for further tumor dissemination. This assumption was underpinned by Battaglia and co-authors [ 10 ] and Heeren and co-authors [ 11 ], who showed that CD8 + FoxP3 + Т cells were more frequent in metastatic tumor-draining lymph nodes in early-stage cervical cancer. Apart from oncological diseases, CD8 Tregs are thought to play an important role in establishment of chronic viral infection, including herpesviruses (EBV, CMV), HCV and HIV (discussed in [ 38 ]).…”

“…However, the data obtained indicated that immunological defects seen in the periphery may accumulate during further CC progression, and additional studies that would include more advanced disease stages are needed to clarify this question. In this regard, some valuable results of a flow cytometric study of cell suspensions prepared from tumor-draining lymph nodes of female patients with stage IB1 cervical cancer [ 11 , 12 ] are worth mentioning: in this study, the authors found altered proportions of CD4 + and CD8 + Т cells, along with altered expression of T-cell activation and immune checkpoint markers, increased frequencies of CD4 + and CD8 + Tregs, as well as a decreased CD3 + CD8 + /Treg ratio.…”

‘DURVIT’: a phase-I trial of single low-dose durvalumab (Medi4736) IntraTumourally injected in cervical cancer: safety, toxicity and effect on the primary tumour- and lymph node microenvironment

“…Furthermore, we reported on the high and interrelated rates of PD-L1 positive myeloid cells and regulatory T cells (Tregs) in metastatic lymph nodes in patients with cervical cancer [ 27 ]. In a comparative study of the immune status of all dissected cervical tumour-draining lymph nodes in five patients, we described that immunosuppression (identified as low CD8+ T cell/ FoxP3+ Treg ratios) may precede actual metastasis, creating niches in the tumour-draining lymphatic catchment area [ 28 ]. These results led to the hypothesis that tumour-associated PD-L1 positive macrophages expand Tregs which subsequently migrate to down-stream lymph nodes to create immune suppressed metastatic niches [ 29 ].…”