经典霍奇金淋巴瘤肿瘤免疫微环境与EB病毒及预后相关性研究

The behavior of classical Hodgkin lymphoma (cHL) was determined by both the intrinsic features of the tumor cells and the characteristics of the microenvironment. In the last few years,an increasing evidence suggests that the tumor immune microenvironment is of prognostic significance in a variety of human maligancies including cHL. For now, cHL patients were assigned to be early or advanced disease based on Ann Arbor staging system and treatment is tailored accordingly. The prognosis of cHL patients substantially improved during the last three decades. However, cHL is clinically heterogeneous that patients with early disease were not consistently associated with a good prognosis.The prognosis of relapsed and refractory cHL patients was poor with a 5-year survival rate of less than 30%. Previous studies proposed that the number of tumor associated macrophages might be a potential biomarkers for the risk prediction in cHL. However,the studies conducted to date were mainly performed in western cHL patients population and were modest in size. Currently, nothing is know in this regard for the Chinese cHL patients. Hence we plan to conduct a pioneering study to investigate the immune cell populations in the tumor microenvironment of cHL in the Chinese population and assess the association of the infiltration intensity of different immune cells with the prognosis. We hope to discover certain prognostic biomarkers for the risk stratification and the selection of risk-adapted individualized treatment in the Chinese cHL patients.

经典霍奇金淋巴瘤（cHL）是一组临床生物学行为异质性明显的肿瘤，目前尚无明确能评估cHL危险度的生物学标记。cHL有着极其丰富和复杂的炎性背景，肿瘤细胞与周围炎症细胞的"对话"机制一直是cHL的研究热点，它不仅对肿瘤的演进起到了不可忽视的重要作用，且近来的研究发现其中的免疫活性细胞成分及功能状态如肿瘤浸润淋巴细胞和肿瘤相关巨噬细胞等，均与预后相关，但这些结果尚需要更多的研究来予以验证。在我国此方面的研究明显滞后，本研究旨在1）比较分析EBV阳性和阴性经典霍奇金淋巴瘤肿瘤微环境内不同亚群浸润淋巴细胞和巨噬细胞分布情况，探讨EBV感染对局部免疫状态的作用；2）结合临床特点，经单因素或多因素分析肿瘤背景中不同免疫细胞亚群的浸润密度对预后的提示意义，初步探寻有意义的预后预测生物学标记，以更好指导临床的个体化治疗。

本研究中，我们利用组织芯片（TMA）技术，对中国北方地区经典霍奇金淋巴瘤（CHL）流行病学特点、与EB病毒感染相关性及肿瘤预后相关生物学标记物进行了研究。获得如下结果：1）对我国青少年CHL病例流行病学特点研究发现，与既往西方文献报道相似，此年龄段病例与EB病毒感染密切相关，特别是年龄14岁以下的少年儿童，且组织学亚型多为混合细胞型。2）本研究发现33%（11/33）的CHL病例存在TNFAIP3（ A20）基因拷贝数减少，且多为EB病毒阴性病例。3）本研究结果显示CHL肿瘤微环境中肿瘤相关巨噬细胞密度与EB病毒感染、组织学亚型密切相关，但未获得其与CHL预后的相关性。4）PD1/PDL1为重要的免疫治疗靶点，本组病例检测PDL-1的表达情况， 65%（34/49）的CHL肿瘤细胞表达PDL-1，且与文献报道一致，其表达与EB病毒感染密切相关。上述结果说明A20基因拷贝数缺失与EB病毒感染负相关；EB病毒阳性与EB病毒阴性CHL病例存在免疫微环境的差异，肿瘤细胞PDL-1的表达对临床免疫靶向治疗具有重要提示意义。