Molecular mechanisms underlying IFN-γ-mediated tumor growth inhibition induced during tumor growth inhibition induced during tumor immunotherapy with rIL-12

Abstract

The present studnt Investigates the molecular by which IFN-_γ produced as a result of in vitroIL-12 addministration exerts its anty-tumor,rIL-12 was administered three or five times into mice bearing CDA1M fibrosarcoma, OV-HM ovarian carcinoma or MCH-1-A1 fibosarcoma. This regimen induced complete regression of CSA1M and OV-HM tumors but only transient growth inhibition of MCH-1-A1 tumors. The anty-tumor effects of Il-12 were associatated with enhanced induction of IFN-_γbecouse these effects were abrogated by pretreatment of hosts with anti-IFN-_γ antibody.Exposure in in vitro of the three types of tumor cells to rIFN-^γ resulted in moderate to potent inhibition of tumor cell growth.IFN^γstimulated the expression of mRNAs for an inducible type of NO synthasa (INOS)in CSA1M cells and indoleamine 2,3-dioxygenasa (IDO), an enzyme capable of degrading tryptophan, in OV-HM cells , but induced only marginal levels of these mRNAs in MCH-I-AL cells. In association withiNOS gene expression, INF-^γ-stimulated CSA1M cells produced a large amount of NO which functioned to inhibit their own growth in vitro. Although OV-HM and MCH-1-A1 cells did not produce NO, they also exhibited NO susceptibility.Whereas the tumor masses from IL-12-treated CSA1M-bearing mice induced higher levels of INOS (for CSA1M) or IDO and iNOS (for OV-HM)mRNAs, the MCH-1-A1 tumor mass expressed lower levels of iNOS mRNA alone.Moreover, massive infiltration of CD4⁺and CD8⁺ T cells and Mac-1⁺ cells was seen only in the CSA1M and OV-HM tumors. Thus, these results indicate that IFN-_γ produced after IL-12 treatment induces the expression of various genes with potential to modulate tumor cells and growth by acting directly on tumore cells or stimulating tumor-infiltrating lymphold cells and that the effectiveness of IL12 therapy is assoiated with the operation if these mechanisms.