可溶性免疫检查点对胃癌患者免疫治疗疗效和预后的预测价值

Predictive value of efficacy and prognosis of soluble immune checkpoints for immunotherapy in patients with gastric cancer

目的探讨可溶性免疫检查点对胃癌患者免疫治疗疗效和预后的预测价值。方法收集2021年4月至2022年7月在南京医科大学附属常州第二人民医院肿瘤中心接受一线SOX化疗联合PD-1抑制剂的胃癌患者的临床资料,检测治疗前、疾病进展时可溶性免疫检查点sIL-2Ra(CD25)、s4-1BB、sCD86、sCTLA4、Free Active TGF-β1、sPD-1、sPD-L1、sTIM-3、sLAG-3、sGalectin-9的浓度。利用Mann-Whitney秩和检验比较疗效评价达部分缓解(PR)组与未达PR组[疾病稳定(SD)+疾病进展(PD)]患者治疗前可溶性免疫检查点差异,Logistic回归分析疗效的独立预测因素,Kaplan-Meier及COX回归分析影响预后的可溶性免疫检查点,Wilcoxon符号秩检验比较治疗前后可溶性免疫检查点的变化。结果共40例患者纳入分析,17例(42.5%)患者疗效评价为PR,17例(42.5%)为SD,6例(15.0%)为PD。PR组患者治疗前sPD-1、sPD-L1、sGalectin-9浓度显著高于疗效未达PR组患者(6.27 pg/mL比3.49 pg/mL,P=0.0043;7.96 pg/mL比7.31 pg/mL,P=0.0014;15083.09 pg/mL比8533.77 pg/mL,P=0.0024)。治疗前血清sPD-1(>4.21 pg/mL)浓度高的患者无进展生存期显著延长(P<0.001,HR0.18,95%CI0.08~0.41,P<0.0001),sPD-1是胃癌患者治疗最佳总体疗效(BOR)的独立预测因子。17例患者疾病进展时sCD86较基线显著增高(74.62 pg/mL比49.71 pg/mL,P=0.0038)。结论sPD-1可作为胃癌患者免疫治疗BOR的预测因子,免疫治疗后sCD86增高可能是免疫治疗耐药的原因。

Objective To explore the predictive value of soluble immune checkpoints for the efficacy and prognosis of immunotherapy in patients with gastric cancer.Methods From April 2021 to July 2022,clinical data of patients with gastric cancer who received first-line SOX chemotherapy combined with PD-1 inhibitor at the Cancer Center of Changzhou No.2 People's Hospital Affiliated to Nanjing Medical University were collected.Concentrations of sIL-2Ra(CD25),s4-1BB,sCD86,sCTLA-4,Free Active TGF-β1,sPD-1,sPD-L1,sTIM-3,sLAG-3,sGalectin-9 were detected before treatment and at the time of disease progression.Mann-Whitney U test was used to compare the differences of soluble immune checkpoints concentration before treatment between patients with partial response(PR)and those without PR[disease stability(SD)+disease progression(PD)].Logistic regression analysis was used to explore independent factors of efficacy prediction.Kaplan-Meier and COX regression analysis were used to explore soluble immune checkpoints affecting prognosis,and Wilcoxon signed-rank test was used to compare the changes of soluble immune checkpoints before and after treatment.Results A total of 40 patients with gastric cancer were incorporated into the analysis,with 17(42.5%)patients evaluated as PR,17(42.5%)as SD,and 6(15.0%)as PD.Before treatment,the concentrations of sPD-1,sPD-L1,and sGalectin-9 in the PR group were significantly higher than those in the SD+PD group(6.27 pg/ml vs.3.49 pg/ml,P=0.0043;7.96 pg/ml vs.7.31 pg/ml,P=0.0014;15083.09 pg/ml vs.8533.77 pg/ml,P=0.0024).Patients with high serum sPD-1 concentration before treatment(sPD-1>4.21 pg/ml)showed significantly longer progression free survival(P<0.001,HR=0.18,95%CI:0.08-0.41,P<0.0001).sPD-1 was an independent predictor of best overall response(BOR)in the treatment of gastric cancer patients.Seventeen patients showed a significant increase in sCD86 at the time of disease progression compared to baseline(74.62 pg/ml vs.49.71 pg/ml,P=0.0038).Conclusion sPD-1 can act as a predictive factor for BOR of immunotherapy in gastric cancer patients,and the increase in sCD86 after immunotherapy may be the reason for immunotherapy resistance.