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.

中文翻译：

---

胃癌中人类白细胞抗原 I 类缺乏：一种在微卫星不稳定肿瘤中最常见的适应性免疫逃避策略。

免疫检查点抑制剂治疗仅对一部分胃癌患者有效。据报道，由人类白细胞抗原 I 类 (HLA-I) 缺陷引起的新抗原呈递受损是免疫逃避的常见机制，与免疫检查点阻断的抵抗力相关。为了阐明 HLA-I 缺陷在胃癌中的重要性，特别关注微卫星不稳定 (MSI) 和 Epstein-Barr 病毒 (EBV) 阳性肿瘤，我们检测了肿瘤细胞上的 HLA-I 表达，并将结果与​​临床病理特征相关联。程序性死亡配体 1 (PD-L1) 表达以及肿瘤浸润免疫细胞的程度。该研究包括 58 个 MSI、44 个 EBV 阳性和 107 个非 EBV 非 MSI 肿瘤进行比较。与 EBV 阳性肿瘤 (23%) 和其他肿瘤 (28%) 相比，MSI 肿瘤 (52%) 中 HLA-I 缺陷（≥1% 肿瘤细胞）的频率显着更高。相反，PD-L1 表达水平在 EBV 阳性肿瘤中最高，其次是 MSI 肿瘤，在肿瘤比例评分和组合阳性评分中，其他肿瘤中的患病率最低。在 MSI 和非 EBV 非 MSI 亚型中，晚期肿瘤 (pT2-4) 中 HLA-I 缺陷的发生率明显高于早期肿瘤 (pT1)。此外，与肿瘤内HLA-I保留的肿瘤区域相比，HLA-I缺陷的肿瘤区域中CD8阳性细胞浸润的程度显着降低。根据我们的观察，HLA-I 以及 PD-L1 应被视为免疫逃逸的常见机制，尤其是在 MSI 亚型中，因此可以作为预测胃癌免疫检查点抑制剂治疗反应的生物标志物。