Journal Article

Classical and non-classical HLA class I aberrations in primary cervical squamous- and adenocarcinomas and paired lymph node metastases

Jordanova, Ekaterina S., Heeren, A. Marijne, Bleeker, Maaike C. G., de Gruijl, Tanja D., Kenter, Gemma G., Ferns, Debbie M., Samuels, Sanne

2016

Overview

BackgroundTumors 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.MethodsClassical (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 Chi2 test 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-Whitney U Test was used to compare the distribution of HLA class I expression between SCC and AC.ResultsDecreased expression of HLA-A (SCC P < 0.001), HLA-B/C (SCC P < 0.01; AC P < 0.01) and total classical HLA (SCC P < 0.001; AC P = 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 (DSS P = 0.001 and P = 0.01; DFS P = 0.003 and P = 0.01, for HLA-A and total classical HLA, respectively).ConclusionThese 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.

• Publisher: BMJ Publishing Group Ltd,BioMed Central,BioMed Central Ltd,BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: Adenocarcinoma / Adenocarcinoma - genetics / Adenocarcinoma - mortality / Adenocarcinoma - pathology / Adult / Aged / Aged, 80 and over / Alleles / Analysis / Antigens / Basic Tumor Immunology / Biomarkers / Cancer / Carcinoma, Squamous Cell - genetics / Carcinoma, Squamous Cell - mortality / Care and treatment / Cervical cancer / Chemotherapy / Classical and non-classical HLA expression / Development and progression / Diagnosis / Female / Gene Expression / Genetic Variation / Gynecology / Health aspects / Histocompatibility antigens / Histocompatibility Antigens Class I - genetics / HLA histocompatibility antigens / Human papillomavirus / Humans / Immune system / Immunohistochemistry / Immunology / Immunotherapy / Kaplan-Meier Estimate / Lymphatic Metastasis / Medicine / Medicine & Public Health / Metastasis / Metastatic lymph nodes / Middle Aged / Neoplasm Staging / Oncology / Pathology / Patients / Primary tumor / Prognosis / Research Article / Squamous cell carcinoma / Survival analysis / Tumor Burden / Uterine Cervical Neoplasms - genetics / Uterine Cervical Neoplasms - mortality / Uterine Cervical Neoplasms - pathology / Young Adult