病理组织和外周血中PD-L1和PD-1表达对侵袭性非霍奇金淋巴瘤患者预后影响的实验研究

发布时间：2018-06-24 07:26

本文选题：PD-L1 + PD-1　；参考：《北京协和医学院》2016年博士论文

【摘要】：背景非霍奇金淋巴瘤(non-Hodgkin lymphoma, NHL)发病率占所有肿瘤的3%-5%；虽然单克隆抗体、小分子靶向药物等新药的应用提高了患者的生存率,但许多患者仍因疾病复发或原发耐药导致治疗失败；且目前T细胞淋巴瘤(T-NHL)尚无标准的一线治疗方案。对NHL发病机制的深入认识是探索新治疗策略关键。程序性细胞死亡配体1 (programmed cell death legend 1, PD-L1/CD274)程序性细胞死亡受体1 (programmed cell death-1, PD-1/CD279)通路作为免疫负调控通路,参与了抑制性肿瘤微环境的形成,使肿瘤细胞获得免疫逃逸；但其在NHL病理过程中的作用研究较少,尚未见PD-L1/PD-1表达对T-NHL预后影响的报导。本课题通过研究病理组织和外周血中PD-L1和PD-1表达对患者临床特征和预后影响,探讨PD-L1/PD-1通路在侵袭性非霍奇金淋巴瘤病理机制中的作用。目的1、明确病理组织PD-L1和PD-1表达对弥漫性大B细胞淋巴瘤(DLBCL)患者临床特征和预后的影响。2、明确病理组织PD-L1和PD-1表达对T-NHL患者临床特征和预后的影响。3、明确外周血可溶性PD-L1和PD-1水平对侵袭性B-NHL患者床特征和预后的影响。方法利用免疫组织化学染色技术,回顾性分析我院新诊断的60例DLBCL(2013年4月至2014年12月)和104例T-NHL(2011年1月至2014年12月)患者病理组织中PD-L1和PD-1的表达,研究其与患者临床特征和预后的相关性。利用酶联免疫吸附测定(ELISA)法,前瞻性研究我院2014年1月至2015年12月新诊断侵袭性B-NHL患者血浆中可溶性PD-L1 (sPD-L1)和PD-1 (sPD-1)水平,分析外周血sPD-L1和sPD-1水平对患者临床特征和预后的影响；并比较其与病理组织PD-L1和PD-1表达的相关性。结果1、部分DLBCL患者病理组织中存在PD-L1和PD-1表达。PD-L1膜表达于肿瘤细胞和及部分浸润的非肿瘤细胞,而PD-1主要膜表达于浸润的淋巴细胞。PD-L1阳性(PD-L1+细胞/所有细胞30%)患者20例(33%)；PD-1阳性(PD-1+细胞／所有细胞5%)患者30例(50%)。PD-L1阳性与non-GCB亚型(P=0.028),低CR率(P=0.023)相关；PD-L1阳性患者PFS (P=0.004)和OS(P=0.021)低于PD-L1阴性患者。而PD-1阳性未能影响患者预后(P=0.310)。2、T-NHL患者病理组织中存在PD-L1高表达。PD-L1阳性患者65例(62%),显著高于DLBCL患者阳性率(P0.000)；而PD-1阳性患者29例(28%),低于DLBCL患者的阳性率(P0.000)。病理组织中PD-L1和PD-1的表达呈负相关(P=0.032)。PD-L1阳性与B症状(P=0.002)、高IPI (P=0.008)、高PIT评分(P=0.008),以及ENKTCL亚型(P=0.025)相关。PD-L1阳性患者PFS (P=0.002)和OS(P=0.001)显著低于PD-L1阴性患者。而PD-1阳性患者OS倾向于较好(P=0.067)。3、侵袭性B-NHL患者血浆sPD-L1显著高于健康对照者(中位值3.79 ng/ml对0.73ng/ml,P0.0001);但sPD-1水平与健康对照者相比无显著差异(P=0.105)。sPD-L1升高与大肿块(P=0.022)和低CR率(P=0.041)相关。高sPD-L1 (4.57 ng/ml)患者的OS差(P=0.006)。但B-NHL患者血浆sPD-L1与病理组织中PD-L1表达未见相关性(P=0.060)。结论1、病理组织PD-L1高表达是DLBCL患者预后不良的危险因素,其有可能作为DLBCL危险分层指标和潜在治疗靶点。2、T-NHL患者病理组织PD-L1表达显著高于DLBCL患者,且与预后不良相关PD-L1高表达可能是T-NHL患者临床更具侵袭性和预后不良的原因之一。4、外周血sPD-L1升高的侵袭性B-NHL患者预后不良；sPD-L1水平变化与治疗反应相关。sPD-L1有可能作为B-NHL患者预后评估和病情监测的生物学标志。
[Abstract]:The incidence of background non Hodgkin lymphoma (non-Hodgkin lymphoma, NHL) accounts for the 3%-5% of all tumors; although the use of new drugs such as monoclonal antibodies and small molecular targeting drugs improves the survival rate of the patients, many patients are still treated for failure due to disease recurrence or primary drug resistance; and T cell lymphoma (T-NHL) has no standard one yet. The deep understanding of the pathogenesis of NHL is the key to exploring new therapeutic strategies. Programmed cell death ligand 1 (programmed cell death legend 1, PD-L1/CD274) programmed cell death receptor 1 (programmed cell death-1, PD-1/CD279) as an immune negative regulation pathway, participates in the formation of inhibitory tumor microenvironment. The effect of PD-L1/PD-1 on the prognosis of T-NHL has not been reported. The effect of the expression of PD-L1 and PD-1 in the pathological tissue and peripheral blood on the clinical characteristics and prognosis of the patients is not seen. The study is to discuss the PD-L1/PD-1 pathway in the invasive non Hodgkin's lymphoma. The role of pathological mechanism. Objective 1 to clarify the effect of PD-L1 and PD-1 expression on the clinical characteristics and prognosis of patients with diffuse large B cell lymphoma (DLBCL)..2, the effect of PD-L1 and PD-1 expression on the clinical characteristics and prognosis of T-NHL patients was clear, and the soluble PD-L1 and PD-1 levels of peripheral blood were determined for invasive B-NHL patients. Methods the expression of PD-L1 and PD-1 in 60 newly diagnosed cases of DLBCL (April 2013 to December 2014) and 104 patients with T-NHL (January 2011 to December 2014) were retrospectively analyzed by immunohistochemical staining. The correlation between the clinical features and the prognosis of the patients was studied. The enzyme linked immunosorbent assay was used. ELISA method was used to prospectively study the levels of soluble PD-L1 (sPD-L1) and PD-1 (sPD-1) in the plasma of the newly diagnosed invasive B-NHL patients from January 2014 to December 2015. The effects of the level of sPD-L1 and sPD-1 in peripheral blood on the clinical characteristics and prognosis of the patients were analyzed, and the correlation with the expression of PD-L1 and PD-1 in the pathological tissue was compared. Results 1, part of the results. In the pathological tissue of DLBCL, the expression of PD-L1 and PD-1 expressed.PD-L1 membrane in tumor cells and partially infiltrated non tumor cells, and the main PD-1 membrane was expressed in the infiltrating lymphocyte.PD-L1 positive (PD-L1+ cell / all cell 30%) patients (33%); PD-1 positive (PD-1+ fine cell / all cell 5%) 30 cases (50%).PD-L1 positive and non-. GCB subtype (P=0.028) and low CR rate (P=0.023) correlation; PFS (P=0.004) and OS (P=0.021) in PD-L1 positive patients were lower than those of PD-L1 negative patients. While PD-1 positive did not affect the prognosis of patients (P=0.310), there were 65 cases (62%) in the pathological tissue of the patients, which was significantly higher than that of the patients. The positive rate of 29 cases (28%) was lower than that of DLBCL patients (P0.000). The expression of PD-L1 and PD-1 in pathological tissues showed negative correlation (P=0.032).PD-L1 positive and B symptom (P=0.002), high IPI (P=0.008), high PIT score (P=0.008), and significantly lower than negative patients. Patients with OS tended to be better (P=0.067).3, and the plasma sPD-L1 in invasive B-NHL patients was significantly higher than that of healthy controls (median value of 3.79 ng/ml to 0.73ng/ml, P0.0001), but the level of sPD-1 was not significantly different from that of healthy controls (P=0.105).SPD-L1 was associated with large masses (P=0.022) and low rates. .006). But there is no correlation between plasma sPD-L1 and PD-L1 expression in pathological tissue (P=0.060). Conclusion 1, the high expression of PD-L1 in pathological tissue is a risk factor for poor prognosis in DLBCL patients. It may be a risk stratification index and potential therapeutic target.2 for DLBCL, and PD-L1 expression in the pathogenesis of T-NHL is significantly higher than that of the DLBCL patients, and the prognosis is higher than that of the prognosis. The high expression of adverse PD-L1 may be one of the more aggressive and poor prognostic factors in T-NHL patients.4, and the aggressive B-NHL patients with elevated peripheral blood sPD-L1 have poor prognosis, and the sPD-L1 level and therapeutic response.SPD-L1 may be a biological marker for the prognosis and monitoring of B-NHL patients.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R733.1

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