Dataset Information

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.

SUBMITTER: Heeren AM

PROVIDER: S-EPMC4741707 | biostudies-other | 2015 Oct

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

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

Heeren A Marijne AM de Boer Eline E Bleeker Maaike C G MC Musters René J P RJ Buist Marrije R MR Kenter Gemma G GG de Gruijl Tanja D TD Jordanova Ekaterina S ES

Oncotarget 20151001 32

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+ ...[more]

PMID: 26431490

Similar Datasets

Project description:Objectives: We aimed to identify the risk factors associated with pelvic lymph node metastasis (LNM) at each anatomic location in patients with stage IB1 cervical cancer. Methods: A primary cohort of 728 patients with stage IB1 cervical cancer who underwent radical hysterectomy and systematic pelvic lymphadenectomy were retrospectively studied. All removed pelvic nodes (N=20,134) were pathologically examined. The risk factors for LNM in different anatomic regions (obturator, internal iliac, external iliac, and common iliac) were evaluated by multivariate logistic regression analyses. Nomograms were generated from the primary cohort and validated in another external cohort (N=242). The performance of the nomogram was assessed by its calibration and discrimination. Overall survival and progression-free survival in patients with different LNM patterns were compared. Results: LNM was found in 266 (1.3%) removed nodes and 106 (14.6%) patients. The incidences of LNM at the obturator, internal iliac, external iliac, common iliac, and parametrial regions were 8.5%, 5.4%, 4.7%, 1.9% and 1.8%, respectively. Among others, tumour size and lymph-vascular space invasion (LVSI), which are preoperatively assessable, were identified as independent risk factors of LNM in the common iliac region and the lower pelvis, respectively, and age was an additional independent risk factor of obturator LNM. The negative predictive values of tumour size <2 cm for common iliac LNM and negative LVSI combined with older age (> 50 years) for obturator LNM were 100% and 98.7%, respectively. A nomogram of these two factors showed good calibration and discrimination (concordance index, 0.761 in the primary cohort and 0.830 in validation cohort). The patients with common iliac LNM had poorer survival than those with LNM confined to the lower pelvis, while the differences in survival between patients with LNM confined to one node, one region or single side and those with more widely spreading LNM were not statistically significant. Conclusions: Tumour size, LVSI and age are region-specific risk factors for pelvic LNM in IB1 cervical cancer, which could be used to allocate the appropriate extent of pelvic lymphadenectomy.

Project description:ImportanceThe presence of pelvic nodal metastases at radical prostatectomy is associated with biochemical recurrence after prostatectomy.ObjectiveTo assess the accuracy of prostate-specific membrane antigen (PSMA) 68Ga-PSMA-11 positron emission tomographic (PET) imaging for the detection of pelvic nodal metastases compared with histopathology at time of radical prostatectomy and pelvic lymph node dissection.Design, setting, and participantsThis investigator-initiated prospective multicenter single-arm open-label phase 3 imaging trial of diagnostic efficacy enrolled 764 patients with intermediate- to high-risk prostate cancer considered for prostatectomy at University of California, San Francisco and University of California, Los Angeles from December 2015 to December 2019. Data analysis took place from October 2018 to July 2021.InterventionsImaging scan with 3 to 7 mCi of 68Ga-PSMA-11 PET.Main outcomes and measuresThe primary end point was the sensitivity and specificity for the detection pelvic lymph nodes compared with histopathology on a per-patient basis using nodal region correlation. Each scan was read centrally by 3 blinded independent central readers, and a majority rule was used for analysis.ResultsA total of 764 men (median [interquartile range] age, 69 [63-73] years) underwent 1 68Ga-PSMA-11 PET imaging scan for primary staging, and 277 of 764 (36%) subsequently underwent prostatectomy with lymph node dissection (efficacy analysis cohort). Based on pathology reports, 75 of 277 patients (27%) had pelvic nodal metastasis. Results of 68Ga-PSMA-11 PET were positive in 40 of 277 (14%), 2 of 277 (1%), and 7 of 277 (3%) of patients for pelvic nodal, extrapelvic nodal, and bone metastatic disease. Sensitivity, specificity, positive predictive value, and negative predictive value for pelvic nodal metastases were 0.40 (95% CI, 0.34-0.46), 0.95 (95% CI, 0.92-0.97), 0.75 (95% CI, 0.70-0.80), and 0.81 (95% CI, 0.76-0.85), respectively. Of the 764 patients, 487 (64%) did not undergo prostatectomy, of which 108 were lost to follow-up. Patients with follow-up instead underwent radiotherapy (262 of 379 [69%]), systemic therapy (82 of 379 [22%]), surveillance (16 of 379 [4%]), or other treatments (19 of 379 [5%]).Conclusions and relevanceThis phase 3 diagnostic efficacy trial found that in men with intermediate- to high-risk prostate cancer who underwent radical prostatectomy and lymph node dissection, the sensitivity and specificity of 68Ga-PSMA-11 PET were 0.40 and 0.95, respectively. This academic collaboration is the largest known to date and formed the foundation of a New Drug Application for 68Ga-PSMA-11.Trial registrationClinicalTrials.gov Identifiers: NCT03368547, NCT02611882, and NCT02919111.

Project description:Purpose: Presence of pelvic lymph node metastases is the main prognostic factor in early stage cervical cancer patients, primarily treated with surgery. Aim of this study was to identify cellular tumor pathways associated with pelvic lymph node metastasis in early stage cervical cancer. Experimental Design: Gene expression profiles (Affymetrix U133 plus 2.0) of 20 patients with negative (N0) and 19 with positive lymph nodes (N+), were compared with gene sets that represent all 285 presently available pathway signatures. Validation immunostaining of tumors of 274 consecutive early stage cervical cancer patients was performed for representatives of the identified pathways. Results: Analysis of 285 pathways resulted in identification of five pathways (TGF-β, NFAT, ALK, BAD, and PAR1) that were dysregulated in the N0, and two pathways (β-catenin and Glycosphingolipid Biosynthesis Neo Lactoseries) in the N+ group. Class comparison analysis revealed that five of 149 genes that were most significantly differentially expressed between N0 and N+ tumors (P<0.001) were involved in β-catenin signaling (TCF4, CTNNAL1, CTNND1/p120, DKK3 and WNT5a). Immunohistochemical validation of two well-known cellular tumor pathways (TGF-β and β-catenin) confirmed that the TGF-β pathway (positivity of Smad4) was related to N0 (OR:0.20, 95%CI:0.06-0.66) and the β-catenin pathway (p120 positivity) to N+ (OR:1.79, 95%CI:1.05-3.05). Conclusions: Our study provides new, validated insights in the molecular mechanism of lymph node metastasis in cervical cancer. Pathway analysis of the microarray expression profile suggested that the TGF-β and p120-associated non-canonical β-catenin pathways are important in pelvic lymph node metastasis in early stage cervical cancer. For the microarray experiment, we selected fresh frozen primary cervical cancer tissue, containing at least 80% tumor cells, of patients with histologically confirmed N0 (n=20) and of patients with N+ (n=19). The N0 and N+ groups were matched for age, FIGO stage and histology (all squamous cell carcinoma).

Project description:BACKGROUND:The ?1,3-N-acetylglucosaminyltransferase-3 gene (B3GNT3) encodes a member of the B3GNT family that functions as the backbone structure of dimeric sialyl-Lewis A and is involved in L-selectin ligand biosynthesis, lymphocyte homing and lymphocyte trafficking. B3GNT3 has been implicated as an important element in the development of certain cancers. However, the characteristics of B3GNT3 in the development and progression of cancer remain largely unknown. Thus, our study aimed to investigate the expression pattern and the prognostic value of B3GNT3 in patients with early-stage cervical cancer. METHODS:The mRNA and protein levels of B3GNT3 expression were examined in eight cervical cancer cell lines and ten paired cervical cancer tumors, using real-time PCR and western blotting, respectively. Immunohistochemistry (IHC) was used to analyze B3GNT3 protein expression in paraffin-embedded tissues from 196 early-stage cervical cancer patients. Statistical analyses were applied to evaluate the association between B3GNT3 expression scores and clinical parameters, as well as patient survival. RESULTS:B3GNT3 expression was significantly upregulated in cervical cancer cell lines and lesions compared with normal cells and adjacent noncancerous cervical tissues. In the 196 cases of tested early-stage cervical cancer samples, the B3GNT3 protein level was positively correlated with high risk TYPES of human papillomavirus (HPV) infection (P = 0.026), FIGO stage (P < 0.001), tumor size (P = 0.025), tumor recurrence (P = 0.004), vital status (P < 0.001), concurrent chemotherapy and radiotherapy (P = 0.016), lymphovascular space involvement (P = 0.003) and most importantly, lymph node metastasis (P = 0.003). Patients with high B3GNT3 expression had a shorter overall survival (OS) and disease-free survival (DFS) compared with those with low expression of this protein. Multivariate analysis suggested that B3GNT3 expression is an independent prognostic indicator for cervical cancer patients. CONCLUSIONS:Our study demonstrated that elevated B3GNT3 expression is associated with pelvic lymph node metastasis and poor outcome in early-stage cervical cancer patients. B3GNT3 may be a novel prognostic marker and therapeutic target for the treatment of cervical cancer.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets