title: Classical and non-classical HLA class I aberrations in primary cervical squamous- and adenocarcinomas and paired lymph node metastases.
abstract: Tumors avoid destruction by cytotoxic T cells (CTL) and natural killer (NK) cells by downregulation of classical human leukocyte antigens (HLA) and overexpression of non-classical HLA. This is the first study to investigate HLA expression in relation to histology (squamous cell carcinoma (SCC) vs. adenocarcinoma (AC)), clinicopathological parameters and survival in a large cervical cancer patient cohort.
  
  
  
  Classical (HLA-A and HLA-B/C)- and non-classical HLA molecules (HLA-E and HLA-G) were studied on primary tumors and paired lymph node (LN) metastases from cervical cancer patients (n= 136) by immunohistochemistry. The Chi2test was used for the comparison of clinicopathological characteristics between SCC and AC patients. The Related-Samples Wilcoxon Signed Rank test was used to compare HLA expression between the primary tumor and metastasis in LN. Patient survival rates were analyzed by Kaplan-Meier curves and Log Rank test. The Mann-WhitneyUTest was used to compare the distribution of HLA class I expression between SCC and AC.
  
  
  
  Decreased expression of HLA-A (SCCP< 0.001), HLA-B/C (SCCP< 0.01; ACP< 0.01) and total classical HLA (SCCP< 0.001; ACP= 0.02) was apparent in metastatic tumor cells compared to the primary tumor. In primary SCC, there was a clear trend towards complete loss of HLA-A (P= 0.05). SCC metastases showed more complete loss of HLA-A, while AC metastases showed more complete loss of HLA-B/C (P= 0.04). In addition, tumor size and parametrium involvement were also related to aberrant HLA class I expression. No significant associations between HLA expression and disease-specific (DSS) or disease-free survival (DFS) were found in this advanced disease cohort. However, in the SCC group, samples showing loss of HLA-A or loss of total classical HLA but positive for HLA-G were linked to poor patient survival (DSSP= 0.001 andP= 0.01; DFSP= 0.003 andP= 0.01, for HLA-A and total classical HLA, respectively).
  
  
  
  These results strengthen the idea of tumor immune escape variants leading to metastasis. Moreover, SCC tumors showing downregulation of HLA-A or total classical HLA in combination with HLA-G expression had poor prognosis. Our findings warrant further analysis of HLA expression as a biomarker for patient selection for CTL- and NK- cell based immunotherapeutic intervention.
authors.affiliation: Center Gynecological Oncology Amsterdam (CGOA), Department of Obstetrics and Gynecology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
authors.forename: Debbie M
authors.initials: DM
authors.lastname: Ferns
authors.affiliation: Center Gynecological Oncology Amsterdam (CGOA), Department of Obstetrics and Gynecology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.|Department of Medical Oncology, VU University Medical Center-Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
authors.forename: A Marijne
authors.initials: AM
authors.lastname: Heeren
authors.affiliation: Center Gynecological Oncology Amsterdam (CGOA), Department of Gynecology, Netherlands Cancer Institute - Antoni van Leeuwenhoek, P.O. Box 90203, 1006 BE Amsterdam, The Netherlands.
authors.forename: Sanne
authors.initials: S
authors.lastname: Samuels
authors.affiliation: Department of Pathology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
authors.forename: Maaike C G
authors.initials: MCG
authors.lastname: Bleeker
authors.affiliation: Department of Medical Oncology, VU University Medical Center-Cancer Center Amsterdam, De Boelelaan 1117, 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, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.|Center Gynecological Oncology Amsterdam (CGOA), Department of Gynecology, Netherlands Cancer Institute - Antoni van Leeuwenhoek, P.O. Box 90203, 1006 BE Amsterdam, The Netherlands.|Center Gynecological Oncology Amsterdam (CGOA), Department of Obstetrics and Gynecology, Amsterdam Medical Center, Meibergdreef 9, 1105 AZ 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, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
authors.forename: Ekaterina S
authors.initials: ES
authors.lastname: Jordanova
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D015415:Biomarkers; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000401:mortality; D005260:Female; D015870:Gene Expression; D014644:Genetic Variation; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D047368:Tumor Burden; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D055815:Young Adult
chemical_list: D015415:Biomarkers; D015395:Histocompatibility Antigens Class I
keywords: Adenocarcinoma; Cervical cancer; Classical and non-classical HLA expression; Metastatic lymph nodes; Primary tumor; Squamous cell carcinoma