病证结合的中医药维持治疗方案干预晚期非小细胞肺癌免疫逃逸的临床研究
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摘要
目的:观察中医病证结合治疗方案在晚期非小细胞肺癌(NSCLC)维持治疗中的疗效,并从免疫逃逸角度阐明其机制。方法:采用前瞻性、自身前后对照设计,将65例一线治疗后疾病控制(完全缓解/部分缓解/疾病稳定)的晚期NSCLC患者进行中医病证结合维持治疗。观察该方案对晚期NSCLC患者疾病进展时间(TTP)的影响,同时检测50名正常人及65例患者治疗前后免疫指标,包括可溶性程序性死亡分子1配体(sPD-L1)、CD4~+CD25~+CD127-调节性T细胞(CD4~+CD25~+CD127-Tregs)的变化,从免疫逃逸角度探索疗效机制。结果:中医病证结合维持治疗晚期NSCLC患者中位TTP 96.0d;晚期NSCLC患者外周血sPD-L1浓度、CD4~+CD25~+CD127-Tregs百分比高于正常人[(0.193±0.068)ng/mL vs (0.119±0.045)ng/mL,P=0.001]、[(3.90±1.21)%vs (2.68±0.88)%,P=0.001];中医维持治疗后sPD-L1、CD4~+CD25~+CD127-Tregs水平均成下降趋势;中医维持治疗后TTP延长组(36例)sPD-L1有效率(下降+稳定)高于未延长组(29例),差异无统计学意义(86.1%vs 75.9%,P=0.424),CD4~+CD25~+CD127-Tregs有效率(下降+稳定)高于未延长组,差异有统计学意义(86.1%vs 68.9%,P=0.034)。结论:中医病证结合维持治疗可以延长晚期NSCLC患者一线治疗后疾病进展时间;其机制可能是通过下调sPD-L1、CD4~+CD25~+CD127-Tregs水平来实现。
Objective: To observe the efficacy of traditional Chinese medicine(TCM) with the combination of diseases and syndrome treatment in the maintenance treatment of advanced non-small cell lung cancer(NSCLC) and elucidate the mechanism from the perspective of immune escape. Methods: The prospective and self-controlled before-after contrast design was used, and the 65 patients of advanced NSCLC whose disease were controlled after first-line treatment(complete remission/partial remission/disease stabilization) were accepted the maintenance treatment of TCM with combination of diseases and syndrome. The effect of time to progress(TTP) of advanced NSCLC patients were observed by TCM with the combination of diseases and syndrome theatment, at the same time, the immune indexes of 50 normal people and 65 patients were measured beforeafter treatment, including soluble progress-ligand~(-1)(sPD-L1) and CD4~+CD25~+CD127-regulatory T cells(CD4~+CD25~+CD127-Tregs), and explored the efficacy mechanism from immuneescape. Results: The TTP of advanced NSCLC patients after the maintenance treatment of TCM was 96 days; The levels of sPD-L1 and CD4~+CD25~+CD127-Tregs in peripheral blood of advanced NSCLC patients were higher than the normal people [(0.193±0.068)ng/mL vs(0.119±0.045)ng/mL, P=0.001], [(3.90±1.21)% vs(2.68±0.88)%, P=0.001]. After maintenance treatment of TCM, both sPD-L1 and CD4~+CD25~+CD127-Tregs decreased, the sPD-L1 effective rate(decrease + stability) of the TTP prolongation group was higher than the non-prolongation group, and existed significantly difference(86.1% vs 75.8%, P=0.424), the CD4~+CD25~+CD127-Tregs effective rate(decrease + stability) of the TTP prolongation group was higher than the non-prolongation group, and existed significantly difference(86.1% vs 68.9%, P=0.034). Conclusion: TCM maintenance therapy can prolong the time of disease progression in advanced NSCLC patients after first-line treatment, and the mechanism may be achieved by the down-regulation of sPD-L1 and CD4~+CD25~+CD127-Tregs levels.
Objective: To observe the efficacy of traditional Chinese medicine(TCM) with the combination of diseases and syndrome treatment in the maintenance treatment of advanced non-small cell lung cancer(NSCLC) and elucidate the mechanism from the perspective of immune escape. Methods: The prospective and self-controlled before-after contrast design was used, and the 65 patients of advanced NSCLC whose disease were controlled after first-line treatment(complete remission/partial remission/disease stabilization) were accepted the maintenance treatment of TCM with combination of diseases and syndrome. The effect of time to progress(TTP) of advanced NSCLC patients were observed by TCM with the combination of diseases and syndrome theatment, at the same time, the immune indexes of 50 normal people and 65 patients were measured beforeafter treatment, including soluble progress-ligand~(-1)(sPD-L1) and CD4~+CD25~+CD127-regulatory T cells(CD4~+CD25~+CD127-Tregs), and explored the efficacy mechanism from immuneescape. Results: The TTP of advanced NSCLC patients after the maintenance treatment of TCM was 96 days; The levels of sPD-L1 and CD4~+CD25~+CD127-Tregs in peripheral blood of advanced NSCLC patients were higher than the normal people [(0.193±0.068)ng/mL vs(0.119±0.045)ng/mL, P=0.001], [(3.90±1.21)% vs(2.68±0.88)%, P=0.001]. After maintenance treatment of TCM, both sPD-L1 and CD4~+CD25~+CD127-Tregs decreased, the sPD-L1 effective rate(decrease + stability) of the TTP prolongation group was higher than the non-prolongation group, and existed significantly difference(86.1% vs 75.8%, P=0.424), the CD4~+CD25~+CD127-Tregs effective rate(decrease + stability) of the TTP prolongation group was higher than the non-prolongation group, and existed significantly difference(86.1% vs 68.9%, P=0.034). Conclusion: TCM maintenance therapy can prolong the time of disease progression in advanced NSCLC patients after first-line treatment, and the mechanism may be achieved by the down-regulation of sPD-L1 and CD4~+CD25~+CD127-Tregs levels.
引文
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[2]PAZ-ARESLG,deMARINIsF,DEDIUM,etal.PARAMOUNT:final overall survival results of the phase III study of maintenance pemeterxed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer.Clin Oncol,2013,31(23):2895-2902
[3]PAZ-ARES L G,ALTUG S,VAURY A T,et al.Final results from a Phase II study of pemetrexed and cisplatin with concurrent thoracic radiation after Pem-Cis induction in patien ts with unresectable locally advanced non-squamous non-small cell lung cancer(NSCLC).Lung Cancer,2015,88(2):160-166
[4]CAPPUZZO F,CIULEANU T,STELMAKH L,et al.Erlotinib as maintenance treatment in a dvanced non-smll-cell lung cancer:a multicentre,randomised,placebo-controcled phase 3 study.Lancet Oncol,2010,11(6):521-529
[5]BOUGHTON B.New SATURN results show survival benefit from erlotinib in NSCLC.California:13th World Conference on Lung Cancer(WCLC),2009
[6]JIANG Y,LIU L S,SHEN L P,et al.Traditional Chinese medicine treatment as maintenance therapy in advanced non-small-cell lung cancer:a randomized controlled trial.Complement Ther Med,2016,2(24):55-62
[7]FREEMAN A,BRIDGE A J,Maruthayanar P,et al.Comparative immune phenotypic analysis of cutaneous squamous cell carcinoma and intraepidermal carcinoma in immune-competent individuals:proportional representation of CD8+T-cells but not Fox P3+regulatory T-cells isassociated with disease stage.PLoS One,2014,9(10):e110928
[8]陈海,毛建平.肿瘤免疫逃逸与T淋巴细胞关系的研究进展.中国生物工程杂志,2012,32(10):86-91
[9]林城,陈雄,刘静楠,等.PD-1/PD-L1信号通路在非小细胞肺癌免疫逃逸及其治疗中的研究进展.中国肺癌杂志,2014,17(10):734-740
[10]支修益,吴一龙,马胜林,等.原发性肺癌诊疗规范(2011年版).中国肺癌杂志,2012,15(12):677-688
[11]PETER G.Staging manual in thoracic oncology.Orange Park,LL,USA:Editorial Rx Press,2009
[12]CFDA.中药新药临床研究指导原则(试行).北京:中国医药科技出版社,2002:217-218
[13]上海市卫生局.上海市中医病证诊疗常规.2版.上海:上海中医药大学出版社,2003:128-129
[14]Shanghai Municipal Public Health Bureau.Shanghai Diagnosis and Treatment Routine of TCM Syndrome.2nd ed.Shanghai:Shanghai University of Traditional Chinese Medicine Press,2003.Chinese
[15]阎永贞,那可,魏晓东.肿瘤免疫逃逸机制的研究进展.复旦学报(医学版),2013,40(5):619-624
[16]王晓景,施敏骅,陈永井.肺癌患者化疗前后外周血s PD-L1变化及其临床意义.江苏医药,2013,39(6):654-657
[17]侯清玉,杨秀萍.肿瘤免疫逃逸的研究进展.中华肿瘤防治杂志,2010,17(3):228-232
[18]陈祚伽,高雅懿,李志远.FOXP3+调节性T细胞.生命科学,2010,22(6):515-528
[19]LIFSHITZ G V,ZHDANOV D D,LOKHONINA A V,et al.Ex vivo expanded regulatory T cells CD4+CD25+Fox P3+CD127 low develop strong immunosuppressive activity in patients with remittingrelapsing multiple sclerosis.Autoimmunity,2016,49(6):388-396