Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
J Immunol. 2011 Nov 15;187(10):5452-62. doi: 10.4049/jimmunol.1003946. Epub 2011 Oct 12.
Gliomas that grow uninhibited in the brain almost never metastasize outside the CNS. The rare occurrences of extracranial metastasis are usually associated with a suppressed immune system. This observation raises the possibility that some gliomas might not grow outside the CNS due to an inherent immune response, We report in this study that the highly malignant F98 Fischer rat undifferentiated glioma, which grows aggressively in the brain, spontaneously regresses when injected live s.c. We found that this regression is immune-mediated and that it markedly enhances the survival or cures rats challenged with the same tumor intracranially either before or after the s.c. live-cell treatment. Adoptive transfer experiments showed the effect was immune-mediated and that the CD8 T cell fraction, which exhibited direct tumor cytotoxicity, was more effective than the CD4 T cell fraction in mediating resistance to intracranial challenge of naive rats. Brain tumors from treated rats exhibited enhanced CD3(+)CD8(+)CD4(-) and CD3(+)CD4(+)CD8(-) T cell infiltration and IFN-γ secretion. The results in the F98 glioma were corroborated in the Lewis rat CNS-1 astrocytoma. In both tumor models, s.c. treatment with live cells was significantly better than immunization with irradiated cells. We propose in this study a location-based immunotherapeutic phenomenon we term "split immunity": a tumor that thrives in an immune-privileged site may be inhibited by injecting live, unmodified tumor cells into a site that is not privileged, generating protective immunity that spreads back to the privileged site. Split immunity could explain several long-standing paradoxes regarding the lack of overt extracranial metastasis in patients with primary brain tumors.
在大脑中不受抑制生长的神经胶质瘤几乎从不向 CNS 以外转移。极少数颅外转移的发生通常与免疫系统受抑制有关。这一观察结果提出了这样一种可能性，即由于固有免疫反应，某些神经胶质瘤可能不会在 CNS 外生长。我们在本研究中报告称，高度恶性的 F98 费希尔大鼠未分化神经胶质瘤在大脑中生长迅速，当活 s.c. 注射时会自发消退。我们发现这种消退是免疫介导的，并且它显著增强了用相同肿瘤颅内挑战的大鼠的存活或治愈，无论是在 s.c. 活细胞治疗之前还是之后。过继转移实验表明，这种效果是免疫介导的，并且具有直接肿瘤细胞毒性的 CD8 T 细胞亚群比介导对未致敏大鼠颅内挑战的 CD4 T 细胞亚群更有效。来自治疗大鼠的脑肿瘤表现出增强的 CD3(+)CD8(+)CD4(-)和 CD3(+)CD4(+)CD8(-)T 细胞浸润和 IFN-γ 分泌。在 F98 神经胶质瘤中的结果在 Lewis 大鼠 CNS-1 星形细胞瘤中得到了证实。在这两种肿瘤模型中，活细胞的 s.c. 治疗明显优于用辐照细胞免疫。我们在本研究中提出了一种基于位置的免疫治疗现象，我们称之为“分裂免疫”：在免疫特权部位茁壮成长的肿瘤可以通过将活的、未经修饰的肿瘤细胞注射到非特权部位来抑制，从而产生保护性免疫，这种免疫会扩散回特权部位。分裂免疫可以解释几个长期存在的关于原发性脑肿瘤患者缺乏明显颅外转移的悖论。
