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

Abstract

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s40425-016-0184-3) contains supplementary material, which is available to authorized users.

The effects of IFITM1 and IFITM3 gene deletion on IFNγ stimulated protein synthesis

“…1). Second, a recent study has highlighted that lowered MHC Class I expression also predicts poor prognosis in cervical cancers [54]. This data is also consistent with several studies that highlight elevated rates of metastatic cancer cell growth in vivo are inversely correlated to MHC Class I expression including deletion of the MHC Class I locus [53].…”

“…1). The recent observation that lowered HLA-A, HLA-B, and HLA-C alleles correlates with poor prognosis and enhanced metastatic growth in cervical cancers [54] is further consistent with the existence of an IFITM1/3:HLA signalling pathway regulating cervical cancer outcomes. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)…”

HLA Class I Antigen Expression in Conjunctival Melanoma Is Not Associated With PD-L1/PD-1 Status

“…tumor thickness), which is concordant with previous investigations in cervical cancer and cutaneous melanoma. 42,43 The association of HLA class I expression with M2 macrophages and CD8 þ T cells suggests a connection of IFN-c with HLA class I expression in the tumor. The cytokine IFN-c, mainly secreted by CD4 Th1, CD8 T lymphocytes, macrophages, and natural killer (NK) cells, 44 is known to be a key modulator of HLA expression.…”

Immune Regulatory Network in Cervical Cancer Development: The Expanding Role of Innate Immunity Mechanisms

“…Cervical cancer cells' ability to withstand NK cell-mediated response is clearly confirmed by the observation that the prevalence of NK cells in CD45(+)-infiltrating leukocytes is greatly reduced with the progression of intraepithelial neoplasia to invasive cancer [32]. In addition to the known mechanisms recruited by cervical cancer cells to escape from NK-mediated recognition (including down-regulation of activating NK-cell receptor ligands MICA/B, ULBPs, or aberrant expression of non-classical HLA-G [43]), inhibition of NK cell activity can be driven by intra-tumoral Tregs, as was confirmed in ex vivo experiments with Tregs and NK cells isolated from primary tumors of cervical cancer patients [44]. Whether these negative processes have any influence on circulating NK cells during the development of cervical cancer remains a poorly studied question.…”