本文選題：PD-L1 + PD-1��； 參考：《北京協(xié)和醫(yī)學(xué)院》2016年博士論文

【摘要】：背景非霍奇金淋巴瘤(non-Hodgkin lymphoma, NHL)發(fā)病率占所有腫瘤的3%-5%；雖然單克隆抗體、小分子靶向藥物等新藥的應(yīng)用提高了患者的生存率,但許多患者仍因疾病復(fù)發(fā)或原發(fā)耐藥導(dǎo)致治療失��；且目前T細胞淋巴瘤(T-NHL)尚無標準的一線治療方案。對NHL發(fā)病機制的深入認識是探索新治療策略關(guān)鍵。程序性細胞死亡配體1 (programmed cell death legend 1, PD-L1/CD274)程序性細胞死亡受體1 (programmed cell death-1, PD-1/CD279)通路作為免疫負調(diào)控通路,參與了抑制性腫瘤微環(huán)境的形成,使腫瘤細胞獲得免疫逃逸；但其在NHL病理過程中的作用研究較少,尚未見PD-L1/PD-1表達對T-NHL預(yù)后影響的報導(dǎo)。本課題通過研究病理組織和外周血中PD-L1和PD-1表達對患者臨床特征和預(yù)后影響,探討PD-L1/PD-1通路在侵襲性非霍奇金淋巴瘤病理機制中的作用。目的1、明確病理組織PD-L1和PD-1表達對彌漫性大B細胞淋巴瘤(DLBCL)患者臨床特征和預(yù)后的影響。2、明確病理組織PD-L1和PD-1表達對T-NHL患者臨床特征和預(yù)后的影響。3、明確外周血可溶性PD-L1和PD-1水平對侵襲性B-NHL患者床特征和預(yù)后的影響。方法利用免疫組織化學(xué)染色技術(shù),回顧性分析我院新診斷的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)患者病理組織中PD-L1和PD-1的表達,研究其與患者臨床特征和預(yù)后的相關(guān)性。利用酶聯(lián)免疫吸附測定(ELISA)法,前瞻性研究我院2014年1月至2015年12月新診斷侵襲性B-NHL患者血漿中可溶性PD-L1 (sPD-L1)和PD-1 (sPD-1)水平,分析外周血sPD-L1和sPD-1水平對患者臨床特征和預(yù)后的影響；并比較其與病理組織PD-L1和PD-1表達的相關(guān)性。結(jié)果1、部分DLBCL患者病理組織中存在PD-L1和PD-1表達。PD-L1膜表達于腫瘤細胞和及部分浸潤的非腫瘤細胞,而PD-1主要膜表達于浸潤的淋巴細胞。PD-L1陽性(PD-L1+細胞/所有細胞30%)患者20例(33%)；PD-1陽性(PD-1+細胞／所有細胞5%)患者30例(50%)。PD-L1陽性與non-GCB亞型(P=0.028),低CR率(P=0.023)相關(guān)；PD-L1陽性患者PFS (P=0.004)和OS(P=0.021)低于PD-L1陰性患者。而PD-1陽性未能影響患者預(yù)后(P=0.310)。2、T-NHL患者病理組織中存在PD-L1高表達。PD-L1陽性患者65例(62%),顯著高于DLBCL患者陽性率(P0.000)；而PD-1陽性患者29例(28%),低于DLBCL患者的陽性率(P0.000)。病理組織中PD-L1和PD-1的表達呈負相關(guān)(P=0.032)。PD-L1陽性與B癥狀(P=0.002)、高IPI (P=0.008)、高PIT評分(P=0.008),以及ENKTCL亞型(P=0.025)相關(guān)。PD-L1陽性患者PFS (P=0.002)和OS(P=0.001)顯著低于PD-L1陰性患者。而PD-1陽性患者OS傾向于較好(P=0.067)。3、侵襲性B-NHL患者血漿sPD-L1顯著高于健康對照者(中位值3.79 ng/ml對0.73ng/ml,P0.0001);但sPD-1水平與健康對照者相比無顯著差異(P=0.105)。sPD-L1升高與大腫塊(P=0.022)和低CR率(P=0.041)相關(guān)。高sPD-L1 (4.57 ng/ml)患者的OS差(P=0.006)。但B-NHL患者血漿sPD-L1與病理組織中PD-L1表達未見相關(guān)性(P=0.060)。結(jié)論1、病理組織PD-L1高表達是DLBCL患者預(yù)后不良的危險因素,其有可能作為DLBCL危險分層指標和潛在治療靶點。2、T-NHL患者病理組織PD-L1表達顯著高于DLBCL患者,且與預(yù)后不良相關(guān)PD-L1高表達可能是T-NHL患者臨床更具侵襲性和預(yù)后不良的原因之一。4、外周血sPD-L1升高的侵襲性B-NHL患者預(yù)后不良；sPD-L1水平變化與治療反應(yīng)相關(guān)。sPD-L1有可能作為B-NHL患者預(yù)后評估和病情監(jiān)測的生物學(xué)標志。
[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.
【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R733.1

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