Cancer cells evade immune detection via programmed cell death 1/programmed cell death-ligand 1 (PD-1/PD-L1) interactions that inactivate T cells. PD-1/PD-L1 blockade has become an important therapy in the anti-cancer armamentarium. However, some patients do not benefit from PD-1/PD-L1 blockade despite expressing PD-L1. Here, we screened 101 gastric cancer (GC) patients at diagnosis and 141 healthy control subjects and reported one such subpopulation of GC patients with rs17718883 polymorphism in PD-L1, resulting in a nonsense P146R mutation. We detected rs17718883 in 44% of healthy control subjects, and rs17718883 was associated with a low susceptibility to GC and better prognosis in GC patients. Structural analysis suggests that the mutation weakens the PD-1:PD-L1 interaction. This was supported by co-culture experiments of T cells, with GC cells showing that the P146R substitution results in interferon (IFN)-γ secretion by T cells and enables T cells to suppress GC cell growth. Similar results with animal gastric tumor models were obtained in vivo. PD-1 monoclonal antibody treatment did not enhance the inhibitory effect of T cells on GC cells expressing PD-L1^P146R in vitro or in vivo. This study suggests that rs17718883 is common and may be used as a biomarker for exclusion from PD-1/PD-L1 blockade therapy.

癌细胞通过使 T 细胞失活的程序性细胞死亡 1/程序性细胞死亡-配体 1 (PD-1/PD-L1) 相互作用来逃避免疫检测。PD-1/PD-L1阻断已成为抗癌药物库中的重要疗法。然而，一些患者尽管表达了 PD-L1，但并未从 PD-1/PD-L1 阻断中获益。在这里，我们筛选了 101 名诊断时的胃癌 (GC) 患者和 141 名健康对照受试者，并报告了这样一个 GC 患者亚群，其在 PD-L1 中具有 rs17718883 多态性，导致无义 P146R 突变。我们在 44% 的健康对照受试者中检测到 rs17718883，并且 rs17718883 与 GC 患者的低 GC 易感性和更好的预后相关。结构分析表明突变削弱了 PD-1:PD-L1 相互作用。这得到了 T 细胞共培养实验的支持，GC 细胞显示 P146R 取代导致 T 细胞分泌干扰素 (IFN)-γ，并使 T 细胞能够抑制 GC 细胞生长。获得了与动物胃肿瘤模型相似的结果体内。PD-1 单克隆抗体治疗在体外或体内均未增强 T 细胞对表达 PD-L1 ^P146R 的 GC 细胞的抑制作用。这项研究表明 rs17718883 很常见，可以用作排除 PD-1/PD-L1 阻断疗法的生物标志物。