title: Split immunity: immune inhibition of rat gliomas by subcutaneous exposure to unmodified live tumor cells.
abstract: 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.
authors: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel. volovitz@yahoo.com
authors: Ilan
authors: I
authors: Volovitz
authors: Yotvat
authors: Y
authors: Marmor
authors: Meir
authors: M
authors: Azulay
authors: Arthur
authors: A
authors: Machlenkin
authors: Ofir
authors: O
authors: Goldberger
authors: Felix
authors: F
authors: Mor
authors: Shimon
authors: S
authors: Slavin
authors: Zvi
authors: Z
authors: Ram
authors: Irun R
authors: IR
authors: Cohen
authors: Lea
authors: L
authors: Eisenbach
mesh_terms: D000818:Animals; D001254:Astrocytoma / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D002454:Cell Differentiation / Q000276:immunology*; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D002999:Clone Cells; D018920:Coculture Techniques; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D005910:Glioma / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology; D007276:Injections, Intraventricular; D007279:Injections, Subcutaneous; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D012878:Skin Neoplasms / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D014407:Tumor Cells, Cultured