PD-1、FOXP3和CSF-1R蛋白表达对霍奇金淋巴瘤患者预后的影响
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摘要
目的:研究集落刺激因子1受体(CSF-1R)、叉头转录因子3(FOXP3)和程序性死亡1(PD-1)蛋白表达对霍奇金淋巴瘤患者预后的影响。方法:记录本院收治的54例霍奇金淋巴瘤患者的临床特征资料和治疗方案。采集患者标本,采用免疫组织化学染色法检测微环境相关的预后因子CSF-1R、FOXP3及PD-1蛋白表达,同时通过原位杂交技术检测EB病毒及其小编码的mRNA(EBER);探讨CSF-1R、FOXP3及PD-1 3种蛋白表达与霍奇金淋巴瘤患者预后的关系,并采用单因素分析和多因素分析(Cox比例风险模型)研究影响霍奇金淋巴瘤患者预后的相关因素。结果:54例霍奇金淋巴瘤患者中,CSF-1R~+22例(40. 74%),FOXP3高表达28例(51. 85%),PD-1~+9例(16. 67%)。单因素分析结果发现,国际预后指数(IPI)评分、EBER和FOXP3蛋白表达是霍奇金淋巴瘤患者无进展生存(PFS)的影响因素(均P <0. 05);临床分期(Ann Arbor分期)、IPI评分、EBER、CSF-1R和FOXP3蛋白表达是患者总生存(OS)的影响因素(均P <0. 05)。多因素分析(Cox比例风险模型)结果发现,EBER状态是霍奇金淋巴瘤患者PFS、OS的影响因素(P <0. 05); FOXP3蛋白表达是患者PFS的影响因素(P <0. 05); Ann Arbor分期、CSF-1R蛋白表达均是患者OS的影响因素(均P <0. 05)。结论:CSF-1R、FOXP3与霍奇金淋巴瘤患者的预后有密切联系,可为该病的靶向治疗提供一定的依据。
Objective : To investigate the effect of the expression of colony-stimulating factor 1 receptor(CSF-1 R),forkhead box protein 3(FOXP3) and programmed death 1(PD-1) protein on the prognosis of patients with Hodgkin's lymphoma. Methods: The clinical features and treatment schemes of 54 patients with Hodgkin's lymphoma treated in our hospital were recorded, the specimens were collected and the relevant micro-environment prognostic factors such as the protein expression of CSF-1 R, FOXP3 and PD-1 were detected by immunohistochemical staining, and EB virus and EB virus-encoded RNA(EBER) were detected by in situ hybridization; the correlation between CSF-1 R, FOXP3, PD-1 protein expression with prognosis of patients with Hodgkin lymphoma were analyzed; both the unvariate analysis and multivariate analysis(using Cox proportional hazard model) were uased to analyze the influence factors of prognosis.Results: Among the 54 cases of Hodgkin's lymphoma,22 cases(40. 74%) were positive for CSF-1 R, 28 cases(51.85%) showed high expression of FOXP3 and 9 cases(16. 67%) were positive for PD-4. Unvariate analysis revealed that the international prognostic index(IPI) score,FBER and FOXP3 protein expression were the effecting factors of progression-free survival(PFS) of patients with Hodgkin's lymphoma(all P < 0. 05); clinical staging(Ann Arbor stage),IPI score,EBER, CSF-1 R and FOXP3 protein expression were the effecting factors of overall survival(OS)(all P<0.05). Multivariate analysis(Cox proportional hazard model) results showed that the EBER state was the effecting factors of PFS and OS in patients with Hodgkin's lymphoma(P <0. 05); the expression of FOXP3 protein was the effecting factors of PFS(P <0. 05); Ann Arbor stage and the expression of CSF-1 R protein were the effecting factors for OS(both P <0. 05). Conclusion: CSF-1 R and FOXP3 closely relate with the prognosis of the patients with Hodgkin's lymphoma, which can provide a basis for targeted therapy of this disease.
Objective : To investigate the effect of the expression of colony-stimulating factor 1 receptor(CSF-1 R),forkhead box protein 3(FOXP3) and programmed death 1(PD-1) protein on the prognosis of patients with Hodgkin's lymphoma. Methods: The clinical features and treatment schemes of 54 patients with Hodgkin's lymphoma treated in our hospital were recorded, the specimens were collected and the relevant micro-environment prognostic factors such as the protein expression of CSF-1 R, FOXP3 and PD-1 were detected by immunohistochemical staining, and EB virus and EB virus-encoded RNA(EBER) were detected by in situ hybridization; the correlation between CSF-1 R, FOXP3, PD-1 protein expression with prognosis of patients with Hodgkin lymphoma were analyzed; both the unvariate analysis and multivariate analysis(using Cox proportional hazard model) were uased to analyze the influence factors of prognosis.Results: Among the 54 cases of Hodgkin's lymphoma,22 cases(40. 74%) were positive for CSF-1 R, 28 cases(51.85%) showed high expression of FOXP3 and 9 cases(16. 67%) were positive for PD-4. Unvariate analysis revealed that the international prognostic index(IPI) score,FBER and FOXP3 protein expression were the effecting factors of progression-free survival(PFS) of patients with Hodgkin's lymphoma(all P < 0. 05); clinical staging(Ann Arbor stage),IPI score,EBER, CSF-1 R and FOXP3 protein expression were the effecting factors of overall survival(OS)(all P<0.05). Multivariate analysis(Cox proportional hazard model) results showed that the EBER state was the effecting factors of PFS and OS in patients with Hodgkin's lymphoma(P <0. 05); the expression of FOXP3 protein was the effecting factors of PFS(P <0. 05); Ann Arbor stage and the expression of CSF-1 R protein were the effecting factors for OS(both P <0. 05). Conclusion: CSF-1 R and FOXP3 closely relate with the prognosis of the patients with Hodgkin's lymphoma, which can provide a basis for targeted therapy of this disease.
引文
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2 Villasboas JC,Ansell SM,Witzig TE.Targeting the PD-1 pathway in patients with relapsed classic Hodgkin lymphoma following allogeneic stem cell transplant is safe and effective Oncotarget,2016;7(11):13260-13264.
3 Ansell SM,Lesokhin AM,Borrello I,et al.PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma.New Engl J Med,2015;372(4):311-319.
4 Polk A,Lu Y,Wang T,et al.Colony-stimulating factor-1 receptor is required for nurse-like cell survival in chronic lymphocytic leukemia.Clin Cancer Res,2016;22(24):6118-6128.
5陈聪,刘芳,张聪,等.IL-12p40、IL-42p70在经典型霍奇金淋巴瘤中的表达及意义.安徽医科大学学报,2015;50(9):1308-1312.
6田丽华,张学美.程序性死亡受体-1及其配体在血液肿瘤中的研究进展.现代肿瘤医学,2017;25(21):3531-3534.
7黄慧强,白冰,高玉环,等.应用聚乙二醇化重组人G-CSF预防淋巴瘤患者化疗后中性粒细胞减少:一项前瞻、多中心、开放性临床研究.中华血液学杂志,2017;38(10):825-830.
8陈新,叶兴安,陈志忠,等.结节性淋巴细胞为主型霍奇金淋巴瘤与经典型霍奇金淋巴瘤中p63表达及临床意义.临床与实验病理学杂志,2015;32(1):52-54.
9赵万红,蒙珊,田村秀人,等.G-CSF在恶性淋巴瘤患者体内诱导ENA-78和IL-8的作用研究.中国实验血液学杂志,2014;22(2):344-348.
10赵宇飞.PD1/PD-L1抑制剂治疗肿瘤.中国肿瘤生物治疗杂志,2017;24(8):904-911.
11单丽珠,宋腾,王华庆,等.造血干细胞移植在复发难治霍奇金淋巴瘤中的若干问题.中国肿瘤临床,2015;42(1):28-31.
12 Koh YW,Jeon YK,Yoon DH,et al.Programmed death 1 expression in the peritumoralmicroenvironment is associated with a poorer prognosis in classical Hodgkin lymphoma.Tumor Biol,2016;37(6):7507-7514.
13 Cannarile MA,Weisser M,Jacob W,et al.Colony-stimulating factor 1 receptor(CSF1R)inhibitors in cancer therapy.J Immunother Cancer,2017;5(1):53.
14王滕滕,李素霞,夏冰,等.微环境相关预后因子在经典型霍奇金淋巴瘤患者中的表达及其对预后的影响.中华医学杂志,2017;97(18):1400-1405.
15李艳芬,朱海燕.经典霍奇金淋巴瘤治疗进展.中国实验血液学杂志,2016;24(4):1237-1240.
2 Villasboas JC,Ansell SM,Witzig TE.Targeting the PD-1 pathway in patients with relapsed classic Hodgkin lymphoma following allogeneic stem cell transplant is safe and effective Oncotarget,2016;7(11):13260-13264.
3 Ansell SM,Lesokhin AM,Borrello I,et al.PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma.New Engl J Med,2015;372(4):311-319.
4 Polk A,Lu Y,Wang T,et al.Colony-stimulating factor-1 receptor is required for nurse-like cell survival in chronic lymphocytic leukemia.Clin Cancer Res,2016;22(24):6118-6128.
5陈聪,刘芳,张聪,等.IL-12p40、IL-42p70在经典型霍奇金淋巴瘤中的表达及意义.安徽医科大学学报,2015;50(9):1308-1312.
6田丽华,张学美.程序性死亡受体-1及其配体在血液肿瘤中的研究进展.现代肿瘤医学,2017;25(21):3531-3534.
7黄慧强,白冰,高玉环,等.应用聚乙二醇化重组人G-CSF预防淋巴瘤患者化疗后中性粒细胞减少:一项前瞻、多中心、开放性临床研究.中华血液学杂志,2017;38(10):825-830.
8陈新,叶兴安,陈志忠,等.结节性淋巴细胞为主型霍奇金淋巴瘤与经典型霍奇金淋巴瘤中p63表达及临床意义.临床与实验病理学杂志,2015;32(1):52-54.
9赵万红,蒙珊,田村秀人,等.G-CSF在恶性淋巴瘤患者体内诱导ENA-78和IL-8的作用研究.中国实验血液学杂志,2014;22(2):344-348.
10赵宇飞.PD1/PD-L1抑制剂治疗肿瘤.中国肿瘤生物治疗杂志,2017;24(8):904-911.
11单丽珠,宋腾,王华庆,等.造血干细胞移植在复发难治霍奇金淋巴瘤中的若干问题.中国肿瘤临床,2015;42(1):28-31.
12 Koh YW,Jeon YK,Yoon DH,et al.Programmed death 1 expression in the peritumoralmicroenvironment is associated with a poorer prognosis in classical Hodgkin lymphoma.Tumor Biol,2016;37(6):7507-7514.
13 Cannarile MA,Weisser M,Jacob W,et al.Colony-stimulating factor 1 receptor(CSF1R)inhibitors in cancer therapy.J Immunother Cancer,2017;5(1):53.
14王滕滕,李素霞,夏冰,等.微环境相关预后因子在经典型霍奇金淋巴瘤患者中的表达及其对预后的影响.中华医学杂志,2017;97(18):1400-1405.
15李艳芬,朱海燕.经典霍奇金淋巴瘤治疗进展.中国实验血液学杂志,2016;24(4):1237-1240.