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IL‐12‐induced tumor regression correlates with in situ activity of IFN‐γ produced by tumor‐infiltrating cells and its secondary induction of anti‐tumor pathways
Author(s) -
Yu WenGong,
Ogawa Makoto,
Mu Jie,
Umehara Kazunari,
Tsujimura Takahiro,
Fujiwara Hiromi,
Hamaoka Toshiyuki
Publication year - 1997
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1002/jlb.62.4.450
Subject(s) - biology , fibrosarcoma , tumor infiltrating lymphocytes , monoclonal antibody , interferon gamma , nitric oxide synthase , immunohistochemistry , cancer research , cytokine , immunotherapy , microbiology and biotechnology , nitric oxide , antibody , immune system , immunology , endocrinology , genetics
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‐γ (IFN‐γ) monoclonal antibody (mAb). We investigated whether anti‐IFN‐γ 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‐γ produced by infiltrating cells. Injection of anti‐IFN‐γ 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‐γ mRNA was expressed inside tumor masses by infiltrating cells after IL‐12 therapy irrespective of whether anti‐IFN‐γ mAb was injected. However, anti‐IFN‐γ 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‐γ‐inducible genes. Immunohistochemical analyses also revealed that the expression of iNOS protein was completely inhibited by anti‐IFN‐γ injection. These results suggest that the implementation of in situ IFN‐γ activity and its secondary induction of antitumor pathways such as iNOS and IP‐10 expression are important processes in the IL‐12‐induced tumor regression. J. Leukoc. Biol. 62: 450–457; 1997.