HLA-E expression and its clinical relevance in human renal cell carcinoma.

Barbara Seliger,Sven Wach,Bernd Wullich,Helge Taubert,Dagmar Quandt,Christine Stoehr,Juergen Bukur,Wolfgang Legal,Simon Jasinski-Bergner,Arndt Hartmann

doi:10.18632/oncotarget.11744

Barbara Seliger, Sven Wach + Show 8 more

Open Access

https://doi.org/10.18632/oncotarget.11744

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Abstract

The non-classical human leukocyte antigen E (HLA-E) expression is frequently overexpressed in tumor diseases, transplants and virus-infected cells and represents an immunomodulatory molecule by binding to the receptors CD94/NKG2A, -B and –C on NK and T cells. Due to its immune suppressive features HLA-E expression might represent an important mechanism of tumors to escape immune surveillance.While an aberrant expression of the non-classical HLA-G antigen in human renal cell carcinoma (RCC) has been demonstrated to be associated with a worse outcome of patients and reduced sensitivity to immune effector cell-mediated cytotoxicity, the expression and function of HLA-E has not yet been analyzed in this tumor entity.Higher levels of HLA-E transcripts were detected in all RCC cell lines and tumor lesions, which were tested in comparison to normal kidney epithelium. Immunohistochemical staining of a tissue microarray (TMA) using the HLA-E-specific monoclonal antibody TFL-033 recognizing the cytoplasmic HLA-E α-chain as monomer revealed a heterogeneous HLA-E expression in RCC lesions with the highest frequency in chromophobe RCC when compared to other RCC subtypes. HLA-E expression did not correlate with the frequency of CD3+, CD4+, CD8+ and FoxP3+ immune cell infiltrations, but showed an inverse correlation with infiltrating CD56+ cells. In contrast to HLA-G, HLA-E expression in RCCs was not statistically significant associated with a decreased disease specific survival. These data suggest that HLA-E overexpression frequently occurs in RCC and correlates with reduced immunogenicity.

Highlights

Tumors have developed different strategies to escape immune surveillance [1], including down-regulation of classical MHC class I antigens and/or components of the antigen processing machinery (APM) [2] or up-regulation of the non-classical human leukocyte antigen (HLA)-G and –E antigens [3]
While HLA-G binds to the inhibitory receptors ILT2, ILT4 and KIR2DL4, human leukocyte antigen E (HLA-E) is the major ligand for the inhibitory natural killer (NK) cell receptor CD94/NKG2A, B and for the activating -C expressed on NK cells and cytotoxic T lymphocytes (CTL) [4, 5] resulting in a reduced immune effector cell mediated cytotoxicity [4, 6]
The results suggest that HLA-E might serve in combination with HLA-G as a prognostic biomarker and its status might contribute to a better selection of a subgroup of renal cell carcinoma (RCC) patients with poor prognosis, who might benefit from individually tailored therapies

Summary

Introduction

Tumors have developed different strategies to escape immune surveillance [1], including down-regulation of classical MHC class I antigens and/or components of the antigen processing machinery (APM) [2] or up-regulation of the non-classical HLA-G and –E antigens [3]. While HLA-G binds to the inhibitory receptors ILT2, ILT4 and KIR2DL4, HLA-E is the major ligand for the inhibitory NK cell receptor CD94/NKG2A,- B and for the activating -C expressed on NK cells and cytotoxic T lymphocytes (CTL) [4, 5] resulting in a reduced immune effector cell mediated cytotoxicity [4, 6]. The non-classical HLA-E mRNA is detected in all nucleated cells, while HLA-E protein is only ubiquitously expressed at low levels on the cell surface of most tissues and presents peptides derived from the conserved leader sequences of HLA-A, - B, -C and –G antigens to HLAE-restricted immune effector cells demonstrating its importance for anti-tumor response [4, 9, 10]. There exists evidence that HLA-E www.impactjournals.com/oncotarget expression could be upregulated by HLA-G [13] resulting in an enhanced immune suppression

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