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Abstract：
OBJECTIVE: Immune tolerance and evasion play a critical role in virus-driven malignancies. However, the phenotype and clinical significance of programmed cell death 1 (PD-1) and its ligands, PD-L1 and PD-L2, in aggressive acquired immunodeficiency syndrome (AIDS)-related non-Hodgkin lymphoma (AR-NHL) remain poorly understood, particularly in the Epstein-Barr virus (EBV)-positive subset.
METHODS: We used in situ hybridization with EBV-encoded RNA (EBER) to assess the EBV status. We performed immunohistochemistry and flow cytometry analysis to evaluate components of the PD-1/PD-L1/L2 pathway in a multi-institutional cohort of 58 patients with AR-NHL and compared EBV-positive and EBV-negative cases.
RESULTS: The prevalence of EBV+ in AR-NHL was 56.9% and was associated with a marked increase in the expression of PD-1/PD-L1/PD-L2 in malignant cells. Patients with AR-NHLs who tested positive for both EBER and PD-1 exhibited lower survival rates compared to those negative for these markers (47.4% vs. 93.8%, p = 0.004). Similarly, patients positive for both EBER and PD-L1 also demonstrated poorer survival (56.5% vs. 93.8%, p = 0.043). Importantly, PD-1 tissue-expression demonstrated independent prognostic significance for overall survival in multivariate analysis and was correlated to elevated levels of LDH (r = 0.313, p = 0.031), increased PD-1+ Tregs (p = 0.006), and robust expression of EBER (r = 0.541, p < 0.001) and PD-L1 (r = 0.354, p = 0.014) expression.
CONCLUSIONS: These data emphasize the importance of PD-1-mediated immune evasion in the complex landscape of immune oncology in AR-NHL co-infected with EBV, and contribute to the diagnostic classification and possible definition of immunotherapeutic strategies for this unique subgroup.
METHODS: We used in situ hybridization with EBV-encoded RNA (EBER) to assess the EBV status. We performed immunohistochemistry and flow cytometry analysis to evaluate components of the PD-1/PD-L1/L2 pathway in a multi-institutional cohort of 58 patients with AR-NHL and compared EBV-positive and EBV-negative cases.
RESULTS: The prevalence of EBV+ in AR-NHL was 56.9% and was associated with a marked increase in the expression of PD-1/PD-L1/PD-L2 in malignant cells. Patients with AR-NHLs who tested positive for both EBER and PD-1 exhibited lower survival rates compared to those negative for these markers (47.4% vs. 93.8%, p = 0.004). Similarly, patients positive for both EBER and PD-L1 also demonstrated poorer survival (56.5% vs. 93.8%, p = 0.043). Importantly, PD-1 tissue-expression demonstrated independent prognostic significance for overall survival in multivariate analysis and was correlated to elevated levels of LDH (r = 0.313, p = 0.031), increased PD-1+ Tregs (p = 0.006), and robust expression of EBER (r = 0.541, p < 0.001) and PD-L1 (r = 0.354, p = 0.014) expression.
CONCLUSIONS: These data emphasize the importance of PD-1-mediated immune evasion in the complex landscape of immune oncology in AR-NHL co-infected with EBV, and contribute to the diagnostic classification and possible definition of immunotherapeutic strategies for this unique subgroup.
摘要：
目的：免疫耐受和逃避在病毒驱动的恶性肿瘤中起关键作用。然而,程序性细胞死亡1（PD-1）及其配体的表型和临床意义，PD-L1和PD-L2在侵袭性获得性免疫缺陷综合征（AIDS）相关的非霍奇金淋巴瘤（AR-NHL）中仍然知之甚少，特别是在EB病毒（EBV）阳性亚群中。
方法：我们使用EBV编码RNA（EBER）的原位杂交来评估EBV状态。我们进行了免疫组织化学和流式细胞术分析，以评估58例AR-NHL患者的多机构队列中PD-1/PD-L1/L2通路的成分，并比较了EBV阳性和EBV阴性病例。
结果：AR-NHL中EBV+的患病率为56.9%，与恶性细胞中PD-1/PD-L1/PD-L2的表达明显增加有关。与这些标志物阴性的患者相比，EBER和PD-1检测阳性的AR-NHL患者的生存率较低（47.4％vs.93.8%,p=0.004)。同样，EBER和PD-L1阳性的患者也表现出较差的生存率(56.5%vs.93.8%,p=0.043)。重要的是,在多变量分析中，PD-1组织表达对总生存期具有独立的预后意义，并且与LDH水平升高相关（r=0.313，p=0.031）。PD-1+Tregs增加（p=0.006），EBER(r=0.541,p<0.001)和PD-L1(r=0.354,p=0.014)表达稳健。
结论：这些数据强调了PD-1介导的免疫逃避在与EBV共感染的AR-NHL免疫肿瘤学复杂环境中的重要性，并有助于该独特亚组的诊断分类和免疫治疗策略的可能定义。
方法：我们使用EBV编码RNA（EBER）的原位杂交来评估EBV状态。我们进行了免疫组织化学和流式细胞术分析，以评估58例AR-NHL患者的多机构队列中PD-1/PD-L1/L2通路的成分，并比较了EBV阳性和EBV阴性病例。
结果：AR-NHL中EBV+的患病率为56.9%，与恶性细胞中PD-1/PD-L1/PD-L2的表达明显增加有关。与这些标志物阴性的患者相比，EBER和PD-1检测阳性的AR-NHL患者的生存率较低（47.4％vs.93.8%,p=0.004)。同样，EBER和PD-L1阳性的患者也表现出较差的生存率(56.5%vs.93.8%,p=0.043)。重要的是,在多变量分析中，PD-1组织表达对总生存期具有独立的预后意义，并且与LDH水平升高相关（r=0.313，p=0.031）。PD-1+Tregs增加（p=0.006），EBER(r=0.541,p<0.001)和PD-L1(r=0.354,p=0.014)表达稳健。
结论：这些数据强调了PD-1介导的免疫逃避在与EBV共感染的AR-NHL免疫肿瘤学复杂环境中的重要性，并有助于该独特亚组的诊断分类和免疫治疗策略的可能定义。
