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

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.

NKG2A Blockade Potentiates CD8 T Cell Immunity Induced by Cancer Vaccines

“…We and others reported a negative correlation of HLA-E on the overall survival of cancer patients (Talebian Yazdi et al, 2016, Gooden et al, 2011, van Esch et al, 2014, Seliger et al, 2016, Andersson et al, 2016, Silva et al, 2011); in particular, the beneficial effect of high CD8 T cell counts within tumor was mitigated by high protein expression of HLA-E (Talebian Yazdi et al, 2016, Gooden et al, 2011). These findings suggested that NKG2A receptor expression on tumor-infiltrating lymphocytes might hamper their function by interaction with HLA-E in the microenvironment.…”

“…HLA-E is ubiquitously expressed at low levels, but very high expression can be found on trophoblasts and ductal epithelial cells in immune-privileged tissues like placenta and testis, respectively. In cancers, HLA-E is frequently overexpressed compared to their non-transformed counterparts, including melanoma and carcinomas of lung, cervix, ovarium, vulva and head/neck (Talebian Yazdi et al, 2016, Gooden et al, 2011, van Esch et al, 2014, Seliger et al, 2016, Andersson et al, 2016, Silva et al, 2011). The physiological function of HLA-E is to present ‘self’ peptides derived from other HLA class I molecules (DeCloux et al, 1997, Kraft et al, 2000, O’Callaghan et al, 1998) and to limit autoimmune reactivity.…”

Modulation of MHC class I surface expression in B16F10 melanoma cells by methylseleninic acid

“…51 In contrast, complexes composed of HLA-E and Prdx5 did not interact with NKG2A and therefore did not downregulate NK cell function. 51 HLA-E might be upregulated in response to cytokines like IFNg 52 suggesting that an upregulation of HLA-E in response to MSA cannot be excluded. Thus, further analyses are required to determine the impact of MSA treatment on the expression of MHC class Ib molecules.…”

NK Cell-Based Immunotherapy in Renal Cell Carcinoma

“…Once the best condition for the combined administration of anti-CTLA4 antibodies and the oncolytic virus was identified in a mouse model of RCC, it was shown that the synergistic effects of the combined therapy required the participation of CD8+ T cells, NK cells, and IFNγ for the anti-tumor response [182]. Interestingly, HLA-E expression has been reported in RCC tumors [183,184]. However, whether the use of anti-NKG2A Abs could benefit RCC patients remains unexplored.…”