Basic Research for The Immuno-genetherapy of Brain Tumors

在各种类型的癌症中，已经研究了使用产生精氨酸的肿瘤细胞增强宿主抗肿瘤反应。然而，中枢神经系统对激活的免疫反应表现出耐受性，这种相对的无反应性可能会降低脑肿瘤免疫治疗的疗效。使用产生白细胞介素-2（IL-2）的9 L大鼠胶质肉瘤细胞（9 L/IL-2），我们检测了皮下（s.c.）和/或颅内（i.c.）肿瘤可以引起对脑肿瘤的增强的免疫应答。同系大鼠对皮下接种的9 L/IL-2细胞有排斥反应，但发达的i.c. 9 L/IL-2肿瘤。I.C.的增长。然而，与野生型肿瘤相比，9 L/IL-2肿瘤显著延迟。I.C.的增长。当大鼠同时皮下接受9 L/IL-2细胞时，野生型肿瘤也受到抑制。此外，大多数接种i.c.与9 L/IL-2细胞同时s.c. 9 L/IL-2细胞。免疫组化分析显示，i.c. 9 L/IL-2肿瘤的表达较s.c. 9 L/IL-2肿瘤细胞的凋亡率明显高于i.c.野生型肿瘤。当大鼠s.c.用9 L/IL-2细胞，颅内9 L/IL-2肿瘤的细胞浸润显著增加至与s.c. 9 L/IL-2肿瘤。本研究为联合应用IL-2基因治疗脑肿瘤提供了可能。免疫接种后直接基因转移到脑肿瘤中。

Enhancement of host antitumor response using cytokine-producing tumor cells has been investigated in various types of cancers. The central nervous system, however, shows tolerance for activated immune reactions, and this relative unresponsiveness may lessen the efficacy of immunotherapy for brain tumors. Using interleukin-2 (IL-2)-producing 9L rat gliosarcoma cells (9L/IL-2), we examined whether secretion of IL-2 from subcutaneous (s.c.) and/or intracranial (i.c.) tumors can elicit augmented immunological response to brain tumors. Syngeneic rats could reject 9L/IL-2 cells inoculated s.c., but developed i.c. 9L/IL-2 tumors. The growth of i.c. 9L/IL-2 tumors was, however, significantly retarded compared with that of wild-type tumors. The growth of i.c. wild-type tumors was also suppressed, when the rats concurrently received 9L/IL-2 cells s.c.. Moreover, most of the rats which inoculated i.c. with 9L/IL-2 cells did not developed brain tumors, when concurrently injected s.c. with 9L/IL-2 cells. Immunohistochemical analysis revealed that migration of CD4- positive T cells, CD8-positive T cells, monocytes/ microglias and macrophages in i.c. 9L/IL-2 tumors was less notable than that in s.c. 9L/IL-2 tumors, but was more significant than that in i.c. wild-type tumors. When the rats were inoculated s.c. with 9L/IL-2 cells, the cellular infiltration into intracranial 9L/IL-2 tumors was markedly augmented to a similar level as found in s.c. 9L/IL-2 tumors. The present study may raise a possibility of a therapeutic strategy for brain tumors by the combinatory expression of IL-2 gene using s.c. immunization followed by the direct gene transfer into brain tumors.