INTERFERON GAMMA-INDEPENDENT REJECTION OF INTERLEUKIN 12-TRANSDUCED CARCINOMA-CELLS REQUIRES CD4(-CELLS AND GRANULOCYTE() T)MACROPHAGE COLONY-STIMULATING FACTOR/

We analyzed the ability of interferon (IFN)-gamma knockout mice (GKO) to reject a colon carcinoma transduced with interleukin (IL)-12 genes (C26/IL-12). Although the absence of IFN-gamma impaired the early resp onse and reduced the time to tumor onset in GKO mice, the overall tumo r take rate was similar to that of BALB/c mice. In GKO mice, C26/IL-12 tumors had a reduced number of infiltrating leukocytes, especially CD 8 and natural killer cells. Analysis of the tumor site, draining nodes , and spleens of GKO mice revealed reduced expression of IFN-inducible protein 10 and monokine induced by gamma-IFN. Despite these defects, GKO mice that rejected C26/IL-12 tumor, and mice that were primed in v ivo with irradiated C26/IL-12 cells, showed the same cytotoxic T lymph ocyte activity but higher production of granulocyte/macrophage colony- stimulating factor (GM-CSF) as compared with control BALB/c mice. Trea tment with monoclonal antibodies against GM-CSF abrogated tumor regres sion in GKO but not in BALB/c mice. CD4 T lymphocytes, which proved un necessary or suppressive during rejection of C26/IL-12 cells in BALB/c mice, were required for tumor rejection in GKO mice. CD4 T cell deple tion was coupled with a decline in GM-CSF expression by lymphocytes in filtrating the tumors or in the draining nodes, and with the reduction and disappearance of granulocytes and CD8 T cells, respectively, in t umor nodules. These results suggest that GM-CSF can substitute for IFN -gamma in maintaining the CD8-polymorphonuclear leukocyte cross-talk t hat is a hallmark of tumor rejection.