Background The programed death ligand-1 combined positive score (PD-L1 CPS), the only FDA-approved biomarker for immune checkpoint inhibitor therapy in gastric cancer (GC) patients, is an important but imperfect predictive biomarker. The molecular characteristics of tumors that influence the PD-L1 CPS are largely unknown and would be helpful for screening patients who would benefit from immunotherapy. Methods PD-L1 immunohistochemistry (IHC) and targeted next-generation sequencing techniques were used to compare genomic alterations in 492 GC patients in two groups (PD-L1 CPS ⩾ 1, positive; CPS < 1, negative). Screened PD-L1 expression-related factors were analyzed for immunotherapy efficacy in three distinct GC cohorts from public databases. Results Positive PD-L1 expression occurred in 40% of GC patients and was associated with a higher proportion of phosphatidylinositol 3-kinase (PI3K), SWItch/Sucrose NonFermentable (SWI/SNF), lysine demethylase (KDM), and DNA (cytosine-5)-methyltransferase (DNMT) (all p < 0.01), pathway alterations. Compared to wild-type GC patients, those with PI3K pathway alterations had a higher response rate (p = 0.002) and durable clinical benefit rate with immunotherapy (p = 0.023, p = 0.038) as well as longer progression-free survival (p = 0.084, p = 0.0076) and overall survival (p = 0.2, p = 0.037) with immunotherapy. Conclusion This study revealed PD-L1 expression-related factors in the tumor genome in a GC cohort. Alterations in the PI3K pathway associated with PD-L1 positivity were shown to be associated with better immunotherapy efficacy in three distinct GC cohorts from public databases. Our results provide a potential avenue for patient selection and rational immune combination development for GC patients.

中文翻译：

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PD-L1 表达相关的 PI3K 通路与胃癌免疫治疗疗效相关。

背景 程序性死亡配体-1 联合阳性评分 (PD-L1 CPS) 是 FDA 批准的唯一用于胃癌 (GC) 患者免疫检查点抑制剂治疗的生物标志物，是一种重要但不完善的预测生物标志物。影响 PD-L1 CPS 的肿瘤分子特征在很大程度上尚不清楚，这有助于筛选从免疫治疗中受益的患者。方法采用PD-L1免疫组织化学（IHC）和靶向二代测序技术比较两组492例GC患者的基因组改变（PD-L1 CPS≥1，阳性；CPS<1，阴性）。在公共数据库中的三个不同的 GC 队列中，分析了筛选的 PD-L1 表达相关因素的免疫治疗效果。结果 40% 的 GC 患者出现 PD-L1 阳性表达，并且与较高比例的磷脂酰肌醇 3-激酶 (PI3K)、SWIitch/不可发酵蔗糖 (SWI/SNF)、赖氨酸脱甲基酶 (KDM) 和 DNA（胞嘧啶- 5)-甲基转移酶 (DNMT)（所有 p < 0.01），途径改变。与野生型GC患者相比，PI3K通路改变的患者具有更高的缓解率（p = 0.002）和免疫治疗的持久临床获益率（p = 0.023，p = 0.038）以及更长的无进展生存期（p = 0.038）。 0.084，p = 0.0076）和免疫治疗的总生存率（p = 0.2，p = 0.037）。结论 这项研究揭示了 GC 队列中肿瘤基因组中 PD-L1 表达相关的因素。在来自公共数据库的三个不同的 GC 队列中，与 PD-L1 阳性相关的 PI3K 通路的改变被证明与更好的免疫治疗效果相关。我们的结果为胃癌患者的患者选择和合理的免疫组合开发提供了潜在的途径。