Systemic administration of rIL-12 induces complete tumor regression and protective immunity: response is correlated with a striking reversal of suppressed IFN-gamma production by anti-tumor T cells.
Unfractionated spleen cells taken from tumor-bearing mice 2 weeks after tumor implantation contained tumor-primed T cells which produced cytokines including IL-2 and IFN-gamma when cultured in vitro. With progressive tumor growth this initial lymphokine-producing capacity decreased. Here, we investigated the ability of IL-12 to (i) restore suppressed IFN-gamma production, (ii) cause tumor regression and (ii) induce anti-tumor protective immunity. Addition of rIL-12 to spleen cell cultures from 4- to 10-week-old tumor-bearing mice resulted in a striking enhancement in the production of IFN-gamma compared with cultures of these cells in the absence of rIL-12 or of normal spleen cells in the presence of rIL-12. Five i.p. injections of rIL-12 into mice bearing s.c. tumors induced complete tumor regression. This was found when rIL-12 was given at early (1-2 weeks), intermediate (4-5 weeks) or even late (7 weeks) stages of tumor growth. Furthermore, IL-12-treated mice which rejected the primary tumor exhibited complete resistance to a rechallenge with the same tumor but did not reject a second syngenetic tumor. Immunohistochemical analyses following IL-12 treatment revealed that CD4+ and CD8+ T cells infiltrate the tumor. More importantly, IFN-gamma mRNA expression was observed in fresh tumor masses from tumor-bearing mice receiving IL-12 treatment. The importance of IFN-gamma was further demonstrated by the observation that the systemic administration of anti-IFN-gamma mAb prior to IL-12 treatment completely abrogated the anti-tumor effect of IL-12. Thus, these results indicate that administration of modest levels of rIL-12 to tumor-bearing mice results in tumor regression through mechanisms involving reversal of suppressed IFN-gamma production by anti-tumor T cells and the establishment of a tumor-specific protective immune response.
Biomedical Research Center, Osaka University Medical School, Japan.
J P
JP
Zou
N
N
Yamamoto
T
T
Fujii
H
H
Takenaka
M
M
Kobayashi
S H
SH
Herrmann
S F
SF
Wolf
H
H
Fujiwara
T
T
Hamaoka
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005354:Fibrosarcoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D007108:Immune Tolerance / Q000187:drug effects*; D007113:Immunity, Innate / Q000187:drug effects; D016130:Immunophenotyping; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000502:physiology; D018664:Interleukin-12 / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008222:Lymphokines / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D012074:Remission Induction; D013154:Spleen / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D008222:Lymphokines; D011994:Recombinant Proteins; D018664:Interleukin-12; D007371:Interferon-gamma