Renner Christoph, Stenner Frank
Department of Biomedicine, University Basel, Basel, Switzerland.
Department of Oncology, University Hospital Basel, Basel, Switzerland.
Front Oncol. 2018 Jun 4;8:193. doi: 10.3389/fonc.2018.00193. eCollection 2018.
Patients with classical Hodgkin lymphoma (cHL) have an impaired cellular immune response as indicated by an anergic reaction against standard recall antigens and a diminished rejection reaction of allogeneic skin transplant. This clinical observation can be linked to the histopathological feature of cHL since the typical pattern of a cHL manifestation is characterized by sparse large CD30 tumor-infiltrating Hodgkin-Reed-Sternberg (HRS) cells that are surrounded by a dense inflammatory immune microenvironment with mixed cellularity. Despite this extensive polymorphous inflammatory infiltrate, there is only a poor antitumor immune response seen to the neoplastic HRS cells. This is primarily mediated by a high expression of PD-L1 and PD-L2 ligands on the HRS cell surface which in turn antagonizes the activity of programmed death-1 (PD-1) antigen-positive T cells. PD-L1/L2 overexpression is caused by gene amplification at the 9p24.1 locus and/or latent Epstein-Barr virus infection present in around 40% of cHL cases. The blockade of the PD-L1/L2-PD-1 pathway by monoclonal antibodies can restore local T cell activity and leads to impressive tumor responses, some of which are long lasting and eventually curative. Another feature of HRS cells is the high CD30 antigen expression. Monoclonal antibody technology allowed for the successful development of CD30-specific immunotoxins, bispecific antibodies, and reprogrammed autologous T cells with the first one already approved for the treatment of high risk or relapsed cHL. Altogether, the discovery of the described pathomechanism of immune suppression and the identification of preferential target antigens has rendered cHL to be a prime subject for the successful development of new immunotherapeutic approaches.
经典型霍奇金淋巴瘤（cHL）患者存在细胞免疫反应受损，表现为对标准回忆抗原的无反应性以及同种异体皮肤移植排斥反应减弱。这一临床观察结果可与cHL的组织病理学特征相关联，因为cHL典型的表现模式以稀疏的大CD30肿瘤浸润性霍奇金-里德-斯腾伯格（HRS）细胞为特征，这些细胞被具有混合细胞成分的致密炎症免疫微环境所包围。尽管存在这种广泛的多形性炎症浸润，但对肿瘤性HRS细胞的抗肿瘤免疫反应却很弱。这主要是由HRS细胞表面PD-L1和PD-L2配体的高表达介导的，这反过来又拮抗程序性死亡-1（PD-1）抗原阳性T细胞的活性。PD-L1/L2过表达是由9p24.1位点的基因扩增和/或约40%的cHL病例中存在的潜伏性EB病毒感染引起的。单克隆抗体阻断PD-L1/L2-PD-1途径可恢复局部T细胞活性，并导致显著的肿瘤反应，其中一些反应是持久的，最终可治愈。HRS细胞的另一个特征是CD30抗原高表达。单克隆抗体技术使得成功开发出CD30特异性免疫毒素、双特异性抗体和重编程自体T细胞成为可能，其中第一种已被批准用于治疗高危或复发的cHL。总之，所描述的免疫抑制发病机制的发现以及优先靶抗原的鉴定使cHL成为成功开发新免疫治疗方法的主要研究对象。
