title: 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.
authors.affiliation: Center Gynecological Oncology Amsterdam (CGOA), Department of Obstetrics and Gynecology, VU University Medical Center, 1081 HV Amsterdam, The Netherlands.|Department of Medical Oncology, VU University Medical Center-Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands.
authors.forename: A Marijne
authors.initials: AM
authors.lastname: Heeren
authors.affiliation: Center Gynecological Oncology Amsterdam (CGOA), Department of Obstetrics and Gynecology, VU University Medical Center, 1081 HV Amsterdam, The Netherlands.
authors.forename: Eline
authors.initials: E
authors.lastname: de Boer
authors.affiliation: Department of Pathology, VU University Medical Center, 1081 HV Amsterdam, The Netherlands.
authors.forename: Maaike C G
authors.initials: MC
authors.lastname: Bleeker
authors.affiliation: Laboratory for Physiology, Institute for Cardiovascular Research, VU University Medical Center, 1081 BT Amsterdam, The Netherlands.
authors.forename: René J P
authors.initials: RJ
authors.lastname: Musters
authors.affiliation: Center Gynecological Oncology Amsterdam (CGOA), Department of Obstetrics and Gynecology, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Marrije R
authors.initials: MR
authors.lastname: Buist
authors.affiliation: Center Gynecological Oncology Amsterdam (CGOA), Department of Obstetrics and Gynecology, VU University Medical Center, 1081 HV Amsterdam, The Netherlands.|Center Gynecological Oncology Amsterdam (CGOA), Department of Obstetrics and Gynecology, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands.|Center Gynecological Oncology Amsterdam (CGOA), Department of Gynecology, Netherlands Cancer Institute - Antoni van Leeuwenhoek, 1006 BE Amsterdam, The Netherlands.
authors.forename: Gemma G
authors.initials: GG
authors.lastname: Kenter
authors.affiliation: Department of Medical Oncology, VU University Medical Center-Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands.
authors.forename: Tanja D
authors.initials: TD
authors.lastname: de Gruijl
authors.affiliation: Center Gynecological Oncology Amsterdam (CGOA), Department of Obstetrics and Gynecology, VU University Medical Center, 1081 HV Amsterdam, The Netherlands.
authors.forename: Ekaterina S
authors.initials: ES
authors.lastname: Jordanova
mesh_terms: D000328:Adult; D060890:B7-H1 Antigen / Q000032:analysis; D014408:Biomarkers, Tumor / Q000032:analysis; D002294:Carcinoma, Squamous Cell / Q000276:immunology* / Q000556:secondary* / Q000601:surgery; D005260:Female; D005455:Fluorescent Antibody Technique; D051858:Forkhead Transcription Factors / Q000032:analysis; D006684:HLA-DR Antigens / Q000032:analysis; D006801:Humans; D007044:Hysterectomy; D016130:Immunophenotyping; D008197:Lymph Node Excision; D008198:Lymph Nodes / Q000276:immunology* / Q000473:pathology / Q000601:surgery; D008207:Lymphatic Metastasis; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000473:pathology; D008875:Middle Aged; D009367:Neoplasm Staging; D010388:Pelvis; D010641:Phenotype; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D019139:Tumor Escape; D002583:Uterine Cervical Neoplasms / Q000276:immunology* / Q000473:pathology* / Q000601:surgery
chemical_list: D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D006684:HLA-DR Antigens
keywords: Immune response; Immunity; Immunology and Microbiology Section; PD-L1-myeloid cells; cervical cancer; metastatic niche; tregs; tumor-draining lymph nodes