Prognostic significance of the immune checkpoint HLA-G/ILT-4 in the survival of patients with gastric cancer

Objective: Human leukocyte antigen-G (HLA-G) and its receptors, including immunoglobulin-like transcripts (ILT)-2 and ILT-4, are closely associated with cancer development and clinical outcomes of patients. However, the clinical significance of HLA-G and ILT-2/-4 in gastric cancer (GC) is limited. Methods: In this study, the percentage of HLA-G-, ILT-2 and ILT-4 positive tumor cells in 127 GC lesion suspensions of tumor cells gated for epithelial cell adhesion molecule (EpCAM) was determined using multicolor flow cytometry and their clinical significance was evaluated. Results: Our data showed that the median percentages of HLA-G-, ILT-2, and ILT-4 expressing GC cells were 18.0%, 67.80%, and 1.42%, respectively, and co-expression of HLA-G/ILT-2, HLA-G/ILT-4, and ILT-2/ILT-4 was 16.9%, 1.42%, and 1.70%, respectively. Kaplan-Meier survival results revealed that besides post-operation N status (p = 0.006), M status (p = 0.001), and AJCC clinical stage (p < 0.001), only high percentage of ILT-4(+) GC cells was a significant factor for worse survival of patients with GC (overall survival [OS]: 42.9 months vs. 84.5 months; p = 0.031). However, among female patients with GC (n = 31), high percentage of either HLA-G(+) (OS: 18.5 months vs. 89.3 months; p = 0.001) or ILT-4(+) (OS: 17.9 months vs. 85.8 months; p = 0.002) GC cells was markedly associated with a poor prognosis. Conclusion: Our findings revealed that among HLA-G, ILT-2, and ILT-4, only a high percentage of ILT-4+ GC cells was significantly related to poor prognosis in the entire cohort of patients with GC. However, high percentage of HLA-G(+) and ILT-4(+) GC cells is associated with poor clinical outcome among female patients with GC.