IL-12-induced tumor regression correlates with in situ activity of IFN-gamma produced by tumor-infiltrating cells and its secondary induction of anti-tumor pathways.
Administration of recombinant interleukin-12 (rIL-12) into CSA1M fibrosarcoma-bearing mice results in complete regression of growing tumors. This tumor regression is associated with massive lymphoid cell infiltration to tumor sites and is completely blocked by injection of anti-interferon-gamma (IFN-gamma) monoclonal antibody (mAb). We investigated whether anti-IFN-gamma mAb exerts its suppressive effect on tumor regression by blocking the IL-12-induced lymphoid cell migration to tumor sites or by inhibiting the secondary effects of IFN-gamma produced by infiltrating cells. Injection of anti-IFN-gamma mAb to CSA1M-bearing mice before IL-12 treatment prevented the induction of tumor regression, whereas this treatment affected only marginally the infiltration of lymphoid cells to tumor masses. In accordance with this, IFN-gamma mRNA was expressed inside tumor masses by infiltrating cells after IL-12 therapy irrespective of whether anti-IFN-gamma mAb was injected. However, anti-IFN-gamma mAb treatment almost completely abrogated the in situ expression of inducible nitric oxide synthase (iNOS) as well as IFN-inducible protein-10 (IP-10) genes as examples of IFN-gamma-inducible genes. Immunohistochemical analyses also revealed that the expression of iNOS protein was completely inhibited by anti-IFN-gamma injection. These results suggest that the implementation of in situ IFN-gamma activity and its secondary induction of anti-tumor pathways such as iNOS and IP-10 expression are important processes in the IL-12-induced tumor regression.
Yu
W G
WG
Biomedical Research Center, Osaka University Medical School, Suita, Japan.
Ogawa
M
M
Mu
J
J
Umehara
K
K
Tsujimura
T
T
Fujiwara
H
H
Hamaoka
T
T
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D054357:Chemokine CXCL10; D018925:Chemokines / Q000096:biosynthesis; D019743:Chemokines, CXC; D015342:DNA Probes; D018076:DNA, Complementary; D005354:Fibrosarcoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000276:immunology*; D018664:Interleukin-12 / Q000627:therapeutic use*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009500:Neutralization Tests; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000627:therapeutic use; D014158:Transcription, Genetic / Q000187:drug effects*
D000911:Antibodies, Monoclonal; D054357:Chemokine CXCL10; D018925:Chemokines; D019743:Chemokines, CXC; D015342:DNA Probes; D018076:DNA, Complementary; D012333:RNA, Messenger; D011994:Recombinant Proteins; D018664:Interleukin-12; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase