Non-classical HLA-class I expression in serous ovarian carcinoma: Correlation with the HLA-genotype, tumor infiltrating immune cells and prognosis

Abstract

In our previous studies, we have shown that patients with serous ovarian carcinoma in advanced surgical stage disease have a particularly poor prognosis if they carry the HLA-A*02 genotype. This represent a stronger prognostic factor than loss or downregulation of the MHC class I heavy chain (HC) on tumor cells. In this study, we investigated the expression of the non-classical, immune tolerogenic HLA -G and -E on the tumor cells along with the infiltration of immune cells in the tumor microenvironment. FFPE primary tumors from 72 patients with advanced stages of serous adenocarcinoma and metastatic cells present in ascites fluid from 8 additional patients were included in this study. Both expression of HLA-G and aberrant expression of HLA-E were correlated to a significant worse prognosis in patients with HLA-A*02, but not with different HLA genotypes. Focal cell expression of HLA-G correlated to a site-specific downregulation of classical MHC class I HC products and aberrant HLA-E expression, showing a poor survival. HLA-G was more frequently expressed in metastatic cells than in primary tumor lesions and the expression of HLA-G inversely correlated with the frequency of tumor infiltrating immune cells. All these parameters can contribute together to identify and discriminate subpopulations of patients with extremely poor prognosis and can give them the opportunity to receive, and benefit of individually tailored treatments.

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.…”

Blocking expression of inhibitory receptor NKG2A overcomes tumor resistance to NK cells

“…Stabilized by peptide loading (24), the HLA-E/peptide complex dampens initial NK cell responses by binding CD94/NKG2A. HLA-E is indeed overexpressed in several tumors (25)(26)(27)(28)(29)(30)(31)(32)(33), and a correlation between higher HLA-E and poorer prognosis has been observed (25,27). Moreover, NKG2A + NK cells are reportedly predominant in the tumor microenvironment.…”

Expression of HLA-DR genes in gliomas: correlation with clinicopathological features and prognosis

“…Aberrant expression of HLA genes has been identified in many human cancers. For instance, overexpression of HLA-G (subtype of HLA class I) has been demonstrated in various human malignancies, such as melanoma, breast cancer, and ovarian cancer [14][15][16][17]. Moreover, correlation of HLA-G overexpression with poor prognosis in low-grade gliomas (LGGs) has also been demonstrated previously by our group [18].…”