Interleukin-6 transduction of a rat T9 glioma clone results in attenuated tumorigenicity and induces glioma immunity in Fischer F344 rats.
We transduced a highly tumorigenic T9 clone (T9.F), isolated from the rat T9 glioblastoma cell line, with a retroviral expression vector containing the human IL-6 cDNA and investigated the effects of IL-6 secretion on glioma formation in the syngeneic Fischer rat. Two subclones producing high and low levels (35 and 3.5 ng/10(6) cells/48 h) of IL-6 were identified and were termed T9.F/IL6/hi and T9.F/IL6/lo, respectively. Subcutaneous (SC) injection of 1 x 10(6) parental T9.F cells resulted in 100% tumor formation and progression. When 1 x 10(6) IL-6 secreting T9.F cells were injected SC, a small palpable tumor formed which sometimes regressed. In this regard, no tumors were detected after 30 days in 76% (13/17) of animals injected with T9.F/IL6/hi cells, whereas only 10% (1/10) of the rats injected with T9.F/IL6/lo cells completely rejected their tumors within this time frame. The addition of an IL-6 neutralizing antibody to the T9.F/IL6/hi SC inoculum followed by an intratumoral injection of the IL-6 neutralizing antibody, seven days later, abrogated the anti-tumor effects. Animals that rejected the IL-6 secreting tumors were 100% protected from subsequent intracranial (IC) challenges with the parental T9.F glioma as well as the original T9 glioblastoma; partially protected from an IC challenge with the unrelated, syngeneic RT-2 glioma; but were not protected from an IC challenge with the syngeneic MadB106 adenocarcinoma. When 1 x 10(4) cells were injected in the brain of naive animals, survival time was significantly increased for those rats implanted with T9.F/IL6/hi cells, but not T9.F/IL6/lo cells, as compared to animals implanted with T9.F parental cells (p = 0.003). This study demonstrates that IL-6 secretion attenuates SC and IC glioma growth and SC rejection of IL-6 secreting T9.F cells induces long-term glioma immunity which is effective in the brain.
Graf
M R
MR
Department of Neurosurgery, Virginia Commonwealth University and Medical College of Virginia, Richmond 23298-0709, USA. mgraf@hsc.vcu.edu
Merchant
R E
RE
D000230:Adenocarcinoma / Q000276:immunology / Q000473:pathology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D000912:Antibodies, Neoplasm / Q000276:immunology / Q000494:pharmacology; D001932:Brain Neoplasms / Q000276:immunology* / Q000473:pathology; D015197:Carcinogenicity Tests; D018076:DNA, Complementary; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D005909:Glioblastoma / Q000276:immunology* / Q000473:pathology; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics* / Q000276:immunology*; D009368:Neoplasm Transplantation; D009500:Neutralization Tests; D051381:Rats; D011916:Rats, Inbred F344; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D012190:Retroviridae / Q000235:genetics; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured / Q000276:immunology / Q000473:pathology / Q000637:transplantation
D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D018076:DNA, Complementary; D015850:Interleukin-6; D011993:Recombinant Fusion Proteins