【摘要】 目的 探讨PD-L1基因多态性对晚期胃癌患者接受PD-1抑制剂单药治疗后疗效的影响。方法 回顾性纳入晚期胃癌患者(n=88)在临床实践中接受PD-1抑制剂(替雷利珠单抗、信迪利单抗和帕博利珠单抗)二线及以上单药治疗的临床资料，并收集具有代表性的晚期胃腺癌患者样本，提取外周血基因组DNA并针对PD-L1基因的多态性位点进行基因分型。通过实时定量PCR测定患者外周血单核细胞中PD-L1 mRNA的相对表达水平。根据实体瘤疗效评价标准(RECIST 1.1)评估肿瘤疗效并计算客观缓解率(objective response rate, ORR)和疾病控制率(disease control rate, DCR),随访患者以绘制生存曲线计算无进展生存期(progression-free survival, PFS)和总生存期(overall survival, OS)。采用χ~2检验或非参数检验比较不同基因型患者的疗效指标和PD-L1的mRNA表达差异，Kaplan-Meier法绘制生存曲线并以对数秩检验比较生存差异，Cox回归模型评估多因素对生存的影响。结果 PD-L1基因rs2297136位点在患者中的基因型分布频率分别为AA型58例(约65.9%)、AG型27例(30.7%)、GG型3例(3.4%),各基因型频率符合Hardy-Weinberg平衡(P=0.998)。基于PD-1抑制剂免疫单药治疗的疗效结果提示总体人群的ORR为13.6%,DCR为45.5%,中位PFS为2.9个月(95%CI:2.5～3.3个月),中位OS为8.9个月(95%CI:6.3～11.5个月)。根据PD-L1基因rs2297136位点的基因型结果提示AG/GG基因型患者的ORR高于AA基因型(23.3%vs 8.6%),差异具有边缘的统计学意义(χ~2=3.631,P=0.057),另外两组患者的DCR分别为66.7%和34.5%,差异具有显著的统计学意义(χ~2=8.262,P=0.004)。生存分析结果提示携带变异等位基因AG/GG患者和AA纯合野生型患者的中位PFS分别为3.3个月和2.8个月(χ~2=2.893,P=0.214),中位OS分别为12.2个月和6.8个月，差异具有显著的统计学意义(χ~2=6.611,P=0.010)。在机制探索方面，不同基因型患者外周血中的PD-L1 mRNA表达存在显著差异：AG/GG基因型患者PD-L1基因mRNA平均表达水平高于AA基因型(P<0.01)。结论 PD-L1通路基因多态性与晚期胃癌免疫治疗疗效密切相关。PD-L1基因rs2297136位点变异可导致PD-L1的mRNA表达上调，进而影响患者对PD-1抑制剂治疗的反应。携带该位点变异的胃癌患者接受PD-1抑制剂治疗具有较好的疗效及预后。PD-L1基因rs2297136多态性有望作为晚期胃癌免疫治疗疗效的预测生物标志物。更多还原

【Abstract】 Objective To investigate the impact of PD-L1 gene polymorphisms on the clinical efficacy of PD-1 inhibitor monotherapy in patients with advanced gastric cancer. Methods Retrospectively, the clinical data of advanced gastric cancer patients who received second-line or later monotherapy with PD-1 inhibitors(Tislelizumab, Sintilimab, or Pembrolizumab) in clinical routine practice were included. Representative samples of advanced gastric adenocarcinoma patients were collected, and genomic DNA from peripheral blood were extracted for genotyping of polymorphic sites of the PD-L1 gene. The relative expression level of PD-L1 mRNA in peripheral blood mononuclear cells of patients was quantified by real-time quantitative PCR. Tumor response was assessed according to RECIST version 1.1, and the objective response rate(ORR) and disease control rate(DCR) were calculated. Patients were followed up to draw survival curves and calculate progression-free survival(PFS) and overall survival(OS). The χ~2 test or non-parametric tests were used to compare efficacy indicators and PD-L1 mRNA expression differences among patients with different genotypes. The Kaplan-Meier method was used to draw survival curves, and the Log-rank test was analyzed and compare survival differences. The Cox regression model was used to evaluate the impact of multiple factors on survival. Results The genotype distribution frequencies of the PD-L1 gene rs2297136 locus in the patients were AA type in 58 patients(approximately 65.9%), AG type in 27 patients(30.7%), and GG type in 3 patients(3.4%), and the genotype frequencies were in accordance with Hardy-Weinberg equilibrium(P=0.998). The efficacy results of PD-1 inhibitor monotherapy-based immunotherapy indicated that the ORR of the entire population was 13.6%, the DCR was 45.5%, the median PFS was 2.9 months(95% CI: 2.5-3.3 months), and the median OS was 8.9 months(95% CI: 6.3-11.5 months). According to the genotype results of the PD-L1 gene rs2297136 locus, the ORR of patients with AG/GG genotypes was higher than that of patients with AA genotype(23.3% vs 8.6%), and the difference was marginally statistically significant(χ~2=3.631, P=0.057). The DCR of the two groups of patients was 66.7% and 34.5%, respectively, and the difference was statistically significant(χ~2=8.262, P=0.004). The survival analysis results indicated that the median PFS of patients carrying the variant allele AG/GG and AA homozygous wild-type patients was 3.3 months and 2.8 months, respectively(χ~2=2.893, P=0.214), and the median OS was 12.2 months and 6.8 months, respectively, and the difference was statistically significant(χ~2=6.611, P=0.010). In terms of mechanism exploration, there were significant differences in PD-L1 mRNA expression in the peripheral blood of patients with different genotypes: the average expression level of PD-L1 gene mRNA in patients with AG/GG genotypes was higher than that in patients with AA genotype(P<0.01). Conclusion The polymorphism of the PD-L1 pathway gene is closely related to the efficacy of immunotherapy for advanced gastric cancer. The variation of the PD-L1 gene rs2297136 locus can lead to the upregulation of PD-L1 mRNA expression, thereby affecting the response of patients to PD-1 inhibitor treatment. Patients with gastric cancer carrying this locus variation have better efficacy and prognosis when treated with PD-1 inhibitors. The polymorphism of the PD-L1 gene rs2297136 locus is expected to be a predictive biomarker for the efficacy of immunotherapy in advanced gastric cancer.更多还原