Basic Research for The Immuno-genetherapy of Brain Tumors

利用产生细胞因子的肿瘤细胞增强宿主抗肿瘤反应的研究已经在各种类型的癌症中进行。然而，中枢神经系统对激活的免疫反应表现出耐受性，这种相对的无反应可能会降低脑瘤免疫治疗的效果。利用产生白介素2(IL-2)的9L大鼠胶质肉瘤细胞(9L/IL-2)，我们检测了皮下(S.C.)和/或颅内(I.C.)肿瘤可以激发对脑肿瘤的增强免疫反应。同基因大鼠可排斥9L/IL-2细胞接种S.C.，但发生I.C.9L/IL-2肿瘤。I.C.的增长。与野生型肿瘤相比，9L/IL-2肿瘤的生长速度明显减慢。I.C.的增长。当同时接受9L/IL-2细胞皮下注射时，野生型肿瘤也受到抑制。此外，大多数接种I.C.的大鼠。同时皮下注射9L/IL-2细胞未发生脑瘤。与9L/IL-2细胞共培养。免疫组织化学分析显示，CD8阳性T细胞、CD8阳性T细胞、单核细胞/小胶质细胞和巨噬细胞在I.C.9L/IL-2肿瘤不如S.C.9L/IL-2肿瘤，但比I.C.野生型肿瘤。大鼠接种S.C.9L/IL-2细胞对颅内9L/IL-2肿瘤的侵袭作用明显增强，与S.C.9L/IL-2肿瘤。本研究为利用S.C.联合表达IL-2基因治疗脑肿瘤提供了可能。免疫后将基因直接转移到脑瘤中。

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.