title: High and interrelated rates of PD-L1+CD14+ antigen-presenting cells and regulatory T cells mark the microenvironment of metastatic lymph nodes from patients with cervical cancer.
abstract: A better understanding of the microenvironment in relation to lymph node metastasis is essential for the development of effective immunotherapeutic strategies against cervical cancer. In the present study, we investigated the microenvironment of tumor-draining lymph nodes of patients with cervical cancer by comprehensive flow cytometry-based phenotyping and enumeration of immune-cell subsets in tumor-negative (LN(-), n = 20) versus tumor-positive lymph nodes (LN(+), n = 8), and by the study of cytokine release profiles (n = 4 for both LN(-) and LN(+)). We found significantly lower CD4(+) and higher CD8(+) T-cell frequencies in LN(+) samples, accompanied by increased surface levels of activation markers (HLA-DR; ICOS; PD-1; CTLA-4) and the memory marker CD45RO. Furthermore, in LN(+), we found increased rates of a potentially regulatory antigen-presenting cell (APC) subset (CD11c(hi)CD14(+)PD-L1(+)) and of myeloid-derived suppressor cell subsets; the LN(+) APC subset correlated with significantly elevated frequencies of FoxP3(+) 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 TNFα but lower levels of IFNγ in LN(+) samples. We conclude that, despite increased T-cell differentiation and activation, a switch to a profound immune-suppressive microenvironment in LN(+) of patients with cervical cancer will enable immune escape. Our data indicate that the CD14(+)PD-L1(+) APC/Treg axis is a particularly attractive and relevant therapeutic target to specifically tackle microenvironmental immune suppression and thus enhances the efficacy of immunotherapy in patients with metastasized cervical cancer.
authors.affiliation: Department of Medical Oncology, VU University Medical Center-Cancer Center Amsterdam, Amsterdam, the Netherlands. Center Gynecological Oncology Amsterdam (CGOA), Department of Obstetrics and Gynecology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: A Marijne
authors.initials: AM
authors.lastname: Heeren
authors.affiliation: Department of Medical Oncology, VU University Medical Center-Cancer Center Amsterdam, Amsterdam, the Netherlands.
authors.forename: Bas D
authors.initials: BD
authors.lastname: Koster
authors.affiliation: Center Gynecological Oncology Amsterdam (CGOA), Department of Gynecology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, the Netherlands.
authors.forename: Sanne
authors.initials: S
authors.lastname: Samuels
authors.affiliation: Center Gynecological Oncology Amsterdam (CGOA), Department of Obstetrics and Gynecology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Debbie M
authors.initials: DM
authors.lastname: Ferns
authors.affiliation: Department of Medical Oncology, VU University Medical Center-Cancer Center Amsterdam, Amsterdam, the Netherlands.
authors.forename: Dafni
authors.initials: D
authors.lastname: Chondronasiou
authors.affiliation: Center Gynecological Oncology Amsterdam (CGOA), Department of Obstetrics and Gynecology, VU University Medical Center, Amsterdam, the Netherlands. Center Gynecological Oncology Amsterdam (CGOA), Department of Gynecology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, the Netherlands.
authors.forename: Gemma G
authors.initials: GG
authors.lastname: Kenter
authors.affiliation: Center Gynecological Oncology Amsterdam (CGOA), Department of Obstetrics and Gynecology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Ekaterina S
authors.initials: ES
authors.lastname: Jordanova
authors.affiliation: Department of Medical Oncology, VU University Medical Center-Cancer Center Amsterdam, Amsterdam, the Netherlands. TD.deGruijl@vumc.nl.
authors.forename: Tanja D
authors.initials: TD
authors.lastname: de Gruijl
mesh_terms: D000328:Adult; D000938:Antigen-Presenting Cells / Q000276:immunology*; D060890:B7-H1 Antigen / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D008207:Lymphatic Metastasis / Q000473:pathology; D008213:Lymphocyte Activation; D008875:Middle Aged; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D059016:Tumor Microenvironment; D002583:Uterine Cervical Neoplasms / Q000276:immunology / Q000473:pathology*; D055815:Young Adult
chemical_list: D060890:B7-H1 Antigen; D016207:Cytokines