Human leukocyte antigen-G isoforms HLA-G2/6, rather than HLA-G1/4/5, are associated with poorer survival in patients with epithelial ovarian cancer

Background The novel immune checkpoint human leukocyte antigen-G (HLA-G) is a promising candidate target for solid cancer immunotherapy. However, knowledge gaps on the clinical relevance of diverse HLA-G isoforms remain. Methods In this study, with the successful generation of monoclonal antibodies (mAbs) against the HLA-G2/6 and HLA-G1/4/5 isoforms, the immunoreactivity scores (IRS) of both HLA-G2/6 and HLA-G1/4/5 expression ( n = 304) were retrospectively analyzed using immunohistochemistry (IHC) in patients with epithelial ovarian cancer (EOC). The significance of the IRS status of HLA-G2/6 and HLA-G1/4/5 related to the clinical variables ( n = 304) and prognosis ( n = 251) of patients with EOC was evaluated. Results The IRS of HLA-G2/6 neg ( n = 7), HLA-G2/6 low ( n = 105), and HLA-G2/6 high ( n = 192) and those of HLA-G1/4/5 neg ( n = 12), HLA-G1/4/5 low ( n = 48), and HLA-G1/4/5 high ( n = 244), respectively. Both HLA-G2/6 high ( p = 0.029) and HLA-G1/4/5 high ( p = 0.016) were the most frequently expressed in other EOC types, followed by the serous and mucinous subtypes. HLA-G2/6 high was remarkably found in patients with advanced pN1 ( p < 0.001), while HLA-G1/4/5 high in patients with advanced pT3 ( p = 0.024). The log-rank Mantel–Cox analysis showed that HLA-G2/6 high was significantly associated with poorer overall survival (OS) (HLA-G2/6 neg/low = 10.0 years vs. HLA-G2/6 high = 6.25years; p = 0.036). Furthermore, patients with HLA-G2/6 high had worse prognosis for those who are elder (>53 years, p = 0.049) and with the serous subtype ( p = 0.028). However, HLA-G2/6 expression was not an independent prognostic risk factor for this EOC cohort. Conclusions Our findings revealed, for the first time, that HLA-G2/6 rather than HLA-G1/4/5 isoform expression is associated with poorer survival in patients with EOC.