Balemans L T, Mattijssen V, Steerenberg P A, Van Driel B E, De Mulder P H, Den Otter W
Laboratory for Pathology, National Institute of Public Health and Environmental Protection, Bilthoven, The Netherlands.
Cancer Immunol Immunother. 1993 Jul;37(1):7-14. doi: 10.1007/BF01516936.
Therapy with repeated intratumoral and perilymphatic administration of relatively low doses of polyethylene-glycol(PEG)-modified interleukin-2 (IL-2) in the syngeneic guinea pig line 10 (L10) hepatocarcinoma results in significant local tumor growth inhibition and a delay in development of regional lymph node metastases of more than 3 weeks when compared to controls. Occasionally animals are cured of tumor. The mechanism of this antitumor activity was studied. The antitumor activity of locoregionally administered PEG-IL-2 was abrogated by pretreatment with polyclonal anti-thymocyte serum, indicating that the observed tumor growth inhibition was a T-cell-mediated phenomenon. Besides the locoregional tumor growth inhibition, a systemic effect was recorded as the growth of a second tumor cell inoculum at the contralateral side was inhibited as well. Furthermore, those animals cured after PEG-IL-2 therapy developed specific immunity against the L10 tumor and this immunity could be transferred to naive animals by spleen cells. Immunohistological observations of the tumor site revealed a slight increase of helper and cytotoxic T cell subpopulations after PEG-IL-2 therapy. More pronounced, however, was the rise in number of eosinophilic granulocytes present in the stroma surrounding the tumor cells. Involvement of cytotoxic cells in the antitumor effects of PEG-IL-2 could not be demonstrated: regional lymph node cells and spleen cells obtained immediately after therapy (day 15) or on day 21 showed no cytotoxic activity in vitro against L10, K562, Daudi and line 1 (L1) target cells. In conclusion, locoregional therapy with PEG-IL-2 induced a a systemic T-cell-mediated antitumor response. As no cytotoxic T cell activity was measured, however, the underlying mechanism is most likely a T-helper response. Eosinophils at the tumor site may be tumoricidal but further experiments must reveal the role of these cells in the PEG-IL-2-induced tumor regression.
在同基因豚鼠10号线（L10）肝癌模型中，采用相对低剂量的聚乙二醇（PEG）修饰白细胞介素-2（IL-2）进行瘤内和淋巴管周围重复给药治疗，与对照组相比，可显著抑制局部肿瘤生长，并使区域淋巴结转移的发生延迟超过3周。偶尔有动物可治愈肿瘤。本研究探讨了这种抗肿瘤活性的机制。局部给予PEG-IL-2的抗肿瘤活性可被多克隆抗胸腺细胞血清预处理所消除，这表明观察到的肿瘤生长抑制是一种T细胞介导的现象。除了局部肿瘤生长抑制外，还记录到一种全身效应，即对侧接种的第二个肿瘤细胞接种物的生长也受到抑制。此外，那些在PEG-IL-2治疗后治愈的动物对L10肿瘤产生了特异性免疫，并且这种免疫可以通过脾细胞转移给未接触过该肿瘤的动物。肿瘤部位的免疫组织学观察显示，PEG-IL-2治疗后辅助性T细胞和细胞毒性T细胞亚群略有增加。然而，更明显的是肿瘤细胞周围基质中嗜酸性粒细胞数量的增加。无法证明细胞毒性细胞参与了PEG-IL-2的抗肿瘤作用：治疗后立即（第15天）或第21天获得的区域淋巴结细胞和脾细胞在体外对L10、K562、Daudi和1号线（L1）靶细胞均无细胞毒性活性。总之，PEG-IL-2局部治疗诱导了一种全身性T细胞介导的抗肿瘤反应。然而，由于未检测到细胞毒性T细胞活性，其潜在机制很可能是T辅助细胞反应。肿瘤部位的嗜酸性粒细胞可能具有杀肿瘤作用，但进一步的实验必须揭示这些细胞在PEG-IL-2诱导的肿瘤消退中的作用。
