Human Leukocyte Antigen Class I Deficiency in Gastric Carcinoma: An Adaptive Immune Evasion Strategy Most Common in Microsatellite Instable Tumors.

Abstract

Immune checkpoint inhibitor therapy is effective only for a subset of patients with gastric cancer. Impaired neoantigen presentation caused by deficiency of human leukocyte antigen class I (HLA-I) has been reported as a common mechanism of immune evasion which is associated with resistance to immune checkpoint blockade. To elucidate the significance of HLA-I deficiency in gastric cancer with special focus on microsatellite instable (MSI) and Epstein-Barr virus (EBV)-positive tumors, we examined HLA-I expression on tumor cells and correlated the results with clinicopathologic features, programmed death-ligand 1 (PD-L1) expression, and degree of tumor-infiltrating immune cells. This study included 58 MSI, 44 EBV-positive, and 107 non-EBV non-MSI tumors for comparison. The frequency of HLA-I deficiency (≥1% tumor cells) was significantly higher in MSI tumors (52%) compared with EBV-positive tumors (23%) and the other tumors (28%). In contrast, PD-L1 expression levels were highest in EBV-positive tumors, followed by MSI tumors, with the lowest prevalence in the other tumors in both Tumor Proportion Score and Combined Positive Score. HLA-I deficiency was significantly more frequent in advanced tumors (pT2-4) than in early tumors (pT1) in MSI and non-EBV non-MSI subtypes. In addition, the degree of CD8-positive cells infiltration was significantly reduced in HLA-I deficient tumor areas compared with HLA-I preserved tumor area within a tumor. Based on our observations, HLA-I, as well as PD-L1, should be considered as a common mechanism of immune escape especially in the MSI subtype, and therefore could be a biomarker predicting response to immune checkpoint inhibitor therapy in gastric cancer.