中晚期恶性肿瘤患者应用PD-1抑制剂多周期治疗对外周血淋巴细胞亚群影响的动态变化研究

目的　研究中晚期恶性肿瘤患者应用程序性死亡受体-1（programmed death recepter-1, PD-1）抑制剂治疗过程中淋巴细胞亚群数量的动态变化，探索 PD-1 抑制剂治疗对患者细胞免疫功能及近期疗效的影响。方法　选取2019 年1 月～ 2021 年1 月入住陕西省人民医院肿瘤内科的144 例接受4 个周期治疗的中晚期恶性肿瘤患者，随机分为PD-1单抗+ 化疗（联合治疗）组（n=54）、PD-1 单抗组（n=38）和化疗组（n=52）。流式细胞术检测患者治疗前及每周期治疗后外周血淋巴细胞亚群:T 细胞(CD3+, CD4+, CD8+)，B 细胞（CD19+）及 NK 细胞（CD16+CD56+）数量，应用重复测量方差分析获得不同治疗方案患者淋巴细胞亚群的动态变化趋势。CT 或磁共振成像（MRI）检查评价治疗前及第4 周期治疗后瘤体大小，根据临床效果评价分为治疗有效组（CR 和 PR）和无效组（SD 和 PD），比较三种治疗方案疗效差异。结果　联合治疗组和 PD-1 单抗治疗组患者外周血 CD3+T, CD4+T, CD4+/CD8+ 细胞数量与治疗前相比显著升高，差异均有统计学意义（F联合治疗组=44.978~315.579, FPD-1 单抗治疗组= 15.174~87.558, 均 P<0.05），CD8+T 细胞数量显著降低，差异有统计学意义（F联合治疗组=636.362， FPD-1 单抗治疗组=189.966, 均 P<0.05）。经过4 个周期治疗，联合治疗组和 PD-1 单抗治疗组患者CD4+T ,CD4+/CD8+ 细胞与化疗组相比显著升高，CD8+T 细胞显著降低，差异均有统计学意义（F=3.365~5.362, 均 P<0.05）；联合治疗组 NK 细胞数量与其他两组治疗方案相比显著升高，差异有统计学意义（F=18.062,P<0.05）；三组治疗方案 B 细胞比较，差异无统计学意义（F=0.434, P>0.05）。联合治疗组和 PD-1 单抗治疗组患者治疗有效率高于化疗组（81.48 %, 84.21 % vs 63.46 %），差异有统计学意义（χ2=6.710, P<0.05）。结论 　PD-1 抑制剂联合化疗或单独使用能显著提高中晚期恶性肿瘤患者的淋巴细胞亚群数量，治疗有效率显著高于化疗组，临床获益优于化疗。

Study on the Dynamic Changes of the Effect of PD-1 Inhibitor Multi-cycle Therapy on Peripheral Blood Lymphocyte Subsets in Patients with Advanced Malignant Tumors

Objective 　To study the dynamic changes of lymphocyte subsets in patients with advanced malignant tumors treated with programmed death receptor-1 (programmed death recepter,PD-1) inhibitor, and evaluate the effect of PD-1 inhibitor on cellular immune function and short-term curative effect. Methods　Selected 144 patients with advanced malignant tumors who were admitted to the department of Oncology, Shaanxi Provincial People’s Hospital, and received 4 cycles of treatment from January 2019 to January 2021. They were randomly divided into PD-1 monoclonal antibody+chemotherapy combination therapy group (54 cases), PD-1 monoclonal antibody group (38 cases) and chemotherapy group (52 cases). The dynamic changes of lymphocyte subsets in peripheral blood of patients before and after treatment were detected by flow cytometry, including T (CD3+, CD4+, CD8+), B cells (CD19+) and NK cells (CD16+CD56+). Repeated measurement analysis of variance (ANOVA) was used to analyze the dynamic change trend of lymphocytes in patients. CT or magnetic resonance imaging (MRI) was used to evaluate the tumor size before and after the fourth cycle of treatment. According to the clinical evaluation of different treatment schemes, the tumor size was divided into effective group (CR and PR) and ineffective group (SD and PD), which used to compare the curative effects of the three treatment schemes. Results　The number of CD3+T, CD4+T and CD4+/CD8+ cells in peripheral blood of 54 patients in combined treatment group and 38 patients in PD-1 McAb treatment group were significantly higher than those before treatment（Fcombined treatment group=44.978~315.579; FPD-1 McAb treatment group=15.174 ～ 87.558, all P<0.05）.The number of CD8+T cells were significantly lower than those before treatment（Fcombined treatment group=636.362, FPD-1 McAb treatment group=189.966, all P<0.05）. After 4 cycles of treatment, the number of CD4+T and CD4+/CD8+ cells in combined treatment group and PD-1 McAb group were significantly higher than those in chemotherapy group, while CD8+T cells were significantly lower than those in chemotherapy group（F=3.365 ～ 5.362, all P<0.05）. The number of NK cells in combined treatment group were significantly higher than those in the other two groups, the difference was statistically significant（F=18.062, P<0.05）, but there was no significant difference in B cells among the three groups, the difference was not statistically significant（F=0.434, P>0.05）. The effective rate in the combination treatment group and PD-1 monoclonal antibody treatment group was significantly higher than that in the chemotherapy group （81.48 %, 84.21 % vs 63.46 %）, the difference was statistically significant（χ2=6.710, P<0.05）. Conclusion　PD-1 inhibitors combined with chemotherapy or alone could significantly increase the number of lymphocyte subsets in patients with aadvanced malignant tumors, the effective rate of treatment was significantly higher than that of chemotherapy group, and the clinical benefit is better than that of chemotherapy.