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

Abstract

<h3>Background</h3> 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. <h3>Methods</h3> 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 (<i>n</i> = 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 <i>U</i> Test was used to compare the distribution of HLA class I expression between SCC and AC. <h3>Results</h3> Decreased expression of HLA-A (SCC <i>P</i> &lt; 0.001), HLA-B/C (SCC <i>P</i> &lt; 0.01; AC <i>P</i> &lt; 0.01) and total classical HLA (SCC <i>P</i> &lt; 0.001; AC <i>P</i> = 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 (<i>P</i> = 0.05). SCC metastases showed more complete loss of HLA-A, while AC metastases showed more complete loss of HLA-B/C (<i>P</i> = 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 <i>P</i> = 0.001 and <i>P</i> = 0.01; DFS <i>P</i> = 0.003 and <i>P</i> = 0.01, for HLA-A and total classical HLA, respectively). <h3>Conclusion</h3> 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.