【作者】 李明；

【导师】 孙萍；

【作者基本信息】 青岛大学 ， 肿瘤学（专业学位）， 2022， 硕士

【摘要】 目的:探索PD-L1表达状态联合CD8~+T/Tregs细胞以及外周血中T细胞亚群的改变在晚期三阴性乳腺癌患者接受免疫治疗联合化疗后的近期疗效预测、预后的价值,以及与不良反应和生活质量之间的相关性。方法:收集2019年9月至2021年2月烟台毓璜顶医院收治的80例PD-L1阳性(CPS评分≥10)的晚期三阴性乳腺癌患者,所有纳入研究的患者均接受免疫治疗联合化疗。对其标本进行免疫组化检测,根据CD8~+T/Tregs细胞比值(比值≥2定义为高比值组)将其分为两组:研究组PD-L1表达阳性且CD8~+T/Tregs细胞高比值与对照组PD-L1表达阳性且CD8~+T/Tregs细胞低比值;抽取患者治疗前、后外周血,应用流式细胞术对外周血进行T细胞亚群分析;按照RECIST 1.1标准进行疗效评价、随访预后及记录不良反应的发生情况,评价两组之间客观缓解率(Objective Response Rate,ORR)、疾病控制率(Disease Control Rate,DCR)、无进展生存时间(Progress Free Survival,PFS)及总生存期(Overall Survival,OS)之间的差异;采用常见不良事件通用术语标准5.0版记录两组发生的不良反应并对其分级;并运用世界卫生组织生活质量(WHOQOL)-100量表对两组患者接受治疗后生活质量进行比较。由此分析免疫组化及流式细胞术检测指标与疗效、预后及免疫相关不良反应、治疗后生活质量之间的关系。结果:对纳入研究的80例患者进行疗效评价发现,研究组的ORR及DCR均显著高于对照组(ORR:60%vs35%,p=0.022;DCR:85%vs60%,p=0.011)。短期内随访结果显示,研究组的中位PFS(9.8个月,95%置信区间8.5个月-11.3个月)较对照组(5.9个月,95%置信区间5.4个月-9.5个月)显著延长3.9个月(p=0.001);至研究结束时另一研究终点OS尚未达到,但研究组的1年OS率为87.5%,较对照组的72.5%升高15%,缺乏统计学意义(p=0.081)。治疗前后患者外周血T细胞亚群进行流式细胞术检测发现:治疗前、后外周血中CD8~+T/Tregs比值与ORR、DCR及PFS无显著相关性,且不影响免疫相关不良反应的发生率;但是治疗后外周血中CD8~+T/Tregs比值阳性组较CD8~+T/Tregs比值阴性组可明显延长患者的1年OS率(90%vs70%,p=0.024)。研究过程中,免疫相关不良反应发生率为70%,两组之间在免疫相关不良反应发生率方面无明显差异。免疫相关不良反应主要包括:反应性毛细血管增生症、天冬氨酸氨基转移酶升高、丙氨酸氨基转移酶升高、甲状腺功能减退、乏力、贫血、胆红素升高、蛋白尿、发热、白细胞减少及其他不良反应。不良反应以1-2级为主,≥3级不良反应发生率为10%;研究期间,无严重免疫相关不良反应死亡事件发生。使用世界卫生组织生活质量-100量表对两组患者进行治疗后生活质量评价:无论是各个领域的得分,还是总分值,研究组均明显高于对照组(p<0.05),说明治疗后研究组患者的生活质量明显优于对照组患者。结论:1.CD8~+T/Tregs比值联合PD-L1表达状态可以预测晚期TNBC患者免疫治疗联合化疗疗效及预后,为免疫治疗联合化疗筛选优势人群:当晚期TNBC患者PD-L1 CPS评分≥10且CD8~+T/Tregs比值≥2时,选择免疫治疗联合化疗方案较其他人群临床获益明显,且在延长无进展生存期基础上并未增加不良反应发生事件的出现,可有效的提高患者生活质量。2.对治疗前后外周血CD8~+T/Tregs细胞比值与上述指标进行相关性分析:治疗后外周血CD8~+T/Tregs细胞比值升高可延长晚期TNBC患者的1年OS率。更多还原

【Abstract】 Purpose:To explore the value of PD-L1 expression status combined with CD8~+T/Tregs cells and the changes of T cells in peripheral blood in predicting the short-term efficacy and prognosis of patients with advanced triple-negative breast cancer after immunotherapy combined with chemotherapy,as well as the correlation with adverse reactions and quality of life.Methods:Eighty patients with PD-L1-positive(CPS score≥10)advanced triple-negative breast cancer admitted to Yantai Yuhuangding Hospital from September 2019 to February2021 were collected,and all patients included in the study received immunotherapy combined with chemotherapy.Their specimens were immunohistochemically examined and divided into two groups according to the CD8~+T/Tregs ratio(ratio≥2 defined as positive).Positive PD-L1 expression and high ratio of CD8~+T/Tregs cells in the study group compared with positive PD-L1 expression and low ratio of CD8~+T/Tregs cells in the control group.Peripheral blood was collected from patients before and after treatment,and T cells were analyzed by flow cytometry in peripheral blood.Efficacy evaluation and follow-up prognosis according to RECIST 1.1 and recording the occurrence of adverse reactions.To evaluate the difference in objective response rate(ORR),disease control rate(DCR),progression-free survival(PFS)and overall survival(OS)between the two groups.Adverse reactions occurring in both groups were recorded and graded using Common Terminology Criteria for Adverse Events version 5.0.The World Health Organization Quality of Life(WHOQOL)-100 scale was used to compare the quality of life of patients in the two groups after treatment.The relationship between immunohistochemical and flow cytometric parameters and efficacy,prognosis and immune-related adverse reactions,and quality of life after treatment was analyzed.Result:Efficacy evaluation of the 80 patients included in the study revealed that the ORR and DCR in the study group were significantly higher than those in the control group(ORR:60%vs 35%,p=0.022;DCR:85%vs 60%,p=0.011).The short-term follow-up results showed that the middle PFS of the study group(9.8 months,95%confidence interval 8.5months-11.3 months)was significantly longer than that of the control group(5.9 months,95%confidence interval 5.4 months-9.5 months)by 3.9 months(p=0.001).The OS,another study endpoint,had not been reached at the end of the study,but the 1-year OS in the study group was 87.5%,15%higher than that of the control group(72.5%),which was not statistically significant(p=0.081).Flow cytometry of peripheral blood T cells before and after treatment revealed that the CD8~+T/Tregs cell ratio in peripheral blood before and after treatment was not significantly correlated with ORR,DCR and PFS,and did not affect the incidence of immune-related adverse reactions.However the 1-year OS rate of patients in the group with positive CD8~+T/Tregs ratio in peripheral blood after treatment can be significantly prolonged(90%vs70%,p=0.024).During the study,the incidence of immune-related adverse reactions was 70%,and there was no significant difference in the incidence of immune-related adverse reactions between the two groups.Immune-related adverse reactions mainly include reactive capillary hyperplasia,aspartate aminotransferase increased,alanine aminotransferase increased,hypothyroidism,asthenia,anemia,bilirubin increased,proteinuria,pyrexia,leukopenia.Adverse reactions were mainly grade 1-2,and the incidence of grade≥3 adverse reactions was 10%.During the study period,no deaths events due to serious immune-related adverse reactions during the study.The quality of life of the two groups was evaluated after treatment using the World Health Organization Quality of Life-100 Scale.The scores of all domains and the total score in the study group were significantly higher than those in the control group(p<0.05),indicating that the quality of life in the study group was significantly better than that in the control group after treatment.Conclusion:1.CD8~+T/Tregs ratio combined with PD-L1 expression status can predict the efficacy and prognosis of immunotherapy combined with chemotherapy in patients with advanced TNBC,which is the dominant population for immunotherapy combined with chemotherapy screening.When the CD8~+T/Tregs ratio is≥2 and PD-L1 CPS score is≥10in TNBC patients,the choice of immunotherapy combined with chemotherapy regimen has significant clinical benefit compared with other populations,and does not increase the occurrence of adverse events on the basis of prolonging progression-free survival,which can effectively improve the quality of life of patients.2.Correlation analysis of peripheral blood CD8~+T/Tregs cell ratio before and after treatment with the above indicators.Elevated CD8~+T/Tregs cell ratio in peripheral blood after treatment prolongs the 1-year OS rate in patients with advanced TNBC.更多还原