Ishida Takashi, Ishii Toshihiko, Inagaki Atsushi, Yano Hiroki, Komatsu Hirokazu, Iida Shinsuke, Inagaki Hiroshi, Ueda Ryuzo
Department of Internal Medicine and Molecular Science and Clinical Pathology, Nagoya City University Graduate School of Medical Sciences, Kawasumi, Mizuho-chou, Mizuho-ku, Nagoya-shi, Aichi, Japan.
Cancer Res. 2006 Jun 1;66(11):5716-22. doi: 10.1158/0008-5472.CAN-06-0261.
Hodgkin lymphoma (HL) is characterized by the presence of a small number of tumor cells in a rich background of inflammatory cells, but the contribution of the abundant nontumor cells to HL pathogenesis is poorly understood. We showed that migratory CD4(+) cells induced by HL cells were hyporesponsive to T-cell receptor stimulation and suppressed the activation/proliferation of the effector CD4(+) T cells in an autologous setting. We further showed that HL cells in the affected lymph nodes were surrounded by a large number of lymphocytes expressing both CC chemokine receptor 4 (CCR4) and FOXP3. These findings indicate that the migratory cells induced by HL cells function as regulatory T (Treg) cells so that these cells create a favorable environment for the tumor cells to escape from host immune system. In addition, we showed that a chimeric anti-CCR4 monoclonal antibody (mAb) could deplete CCR4(+) T cells and inhibit the migration of CD4(+)CD25(+) T cells in vitro. Recognition of the importance of CCR4(+) Treg cells in the pathogenesis of HL will allow rational design of more effective treatments, such as use of an anti-CCR4 mAb, to overcome the suppressive effect of CCR4(+) Treg cells on the host immune response to tumor cells.
霍奇金淋巴瘤（HL）的特征是在丰富的炎症细胞背景中存在少量肿瘤细胞，但大量非肿瘤细胞对HL发病机制的作用却知之甚少。我们发现，HL细胞诱导的迁移性CD4(+)细胞对T细胞受体刺激反应低下，并在自体环境中抑制效应性CD4(+) T细胞的活化/增殖。我们进一步发现，受累淋巴结中的HL细胞被大量同时表达CC趋化因子受体4（CCR4）和FOXP3的淋巴细胞所包围。这些发现表明，HL细胞诱导的迁移性细胞发挥调节性T（Treg）细胞的功能，从而为肿瘤细胞营造一个有利于其逃避宿主免疫系统的环境。此外，我们还表明，一种嵌合抗CCR4单克隆抗体（mAb）能够在体外清除CCR4(+) T细胞并抑制CD4(+)CD25(+) T细胞的迁移。认识到CCR4(+) Treg细胞在HL发病机制中的重要性，将有助于合理设计更有效的治疗方法，如使用抗CCR4 mAb，以克服CCR4(+) Treg细胞对宿主针对肿瘤细胞的免疫反应的抑制作用。
