Mark the Microenvironment of Metastatic Lymph Nodes from Patients with Cervical Cancer

A better understanding of the microenvironment in relation to lymph node metastasis is essential for the development of effec-tive immunotherapeutic strategies against cervical cancer. In the present study, we investigated the microenvironment of tumor-draining lymph nodes of patients with cervical cancer by com-prehensive flow cytometry–based phenotyping and enumeration of immune-cell subsets in tumor-negative (LN, n 20) versus tumor-positive lymph nodes (LNþ, n 8), and by the study of cytokine release profiles (n 4 for both LN and LNþ). We found significantly lower CD4þ and higher CD8þ T-cell frequencies in LNþ samples, accompanied by increased surface levels of activa-tion markers (HLA-DR; ICOS; PD-1; CTLA-4) and the memory marker CD45RO. Furthermore, in LNþ, we found increased rates of a potentially regulatory antigen-presenting cell (APC) subset (CD11chiCD14þPD-L1þ) and of myeloid-derived suppressor cell subsets; the LNþ APC subset correlated with significantly elevated frequencies of FoxP3þ regulatory T cells (Treg). After in vitro stimulation with different Toll-like receptor (TLR) ligands (PGN; Poly-IC; R848),we observed higher production levels of IL6, IL10, and TNFa but lower levels of IFNg in LNþ samples. We conclude that, despite increased T-cell differentiation and activation, a switch to a profound immune-suppressive microenvironment in LNþ of patients with cervical cancer will enable immune escape. Our data indicate that the CD14þPD-L1þ APC/Treg axis is a particularly attractive and relevant therapeutic target to specifi-cally tackle microenvironmental immune suppression and thus enhances the efficacy of immunotherapy in patients with metas-tasized cervical cancer. Cancer Immunol Res; 3(1); 48–58.2014 AACR