Interferon γ–independent Rejection of Interleukin 12–transduced Carcinoma Cells Requires CD4+T Cells and Granulocyte/Macrophage Colony– stimulating Factor

We analyzed the ability of interferon (IFN)-
γ knockout mice (GKO) to reject a colon carcinoma
transduced with interleukin (IL)-12 genes (C26/IL-12). Although the absence of IFN-γ
impaired the early response and reduced the time to tumor onset in GKO mice, the overall tumor
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 CD8 and natural killer cells. Analysis of the
tumor site, draining nodes, and spleens of GKO mice revealed reduced expression of IFNinducible
protein 10 and monokine induced by
γ-IFN. Despite these defects, GKO mice that
rejected C26/IL-12 tumor, and mice that were primed in vivo with irradiated C26/IL-12 cells,
showed the same cytotoxic T lymphocyte activity but higher production of granulocyte/macrophage
colony–stimulating factor (GM-CSF) as compared with control BALB/c mice. Treatment
with monoclonal antibodies against GM-CSF abrogated tumor regression in GKO but
not in BALB/c mice. CD4 T lymphocytes, which proved unnecessary or suppressive during
rejection of C26/IL-12 cells in BALB/c mice, were required for tumor rejection in GKO
mice. CD4 T cell depletion was coupled with a decline in GM-CSF expression by lymphocytes
infiltrating the tumors or in the draining nodes, and with the reduction and disappearance
of granulocytes and CD8 T cells, respectively, in tumor nodules. These results suggest that
GM-CSF can substitute for IFN-γ
in maintaining the CD8–polymorphonuclear leukocyte
cross-talk that is a hallmark of tumor rejection.

Citation:
Zilocchi, C. et al. (1998) ‘Interferon γ–independent Rejection of Interleukin 12–transduced Carcinoma Cells Requires CD4+T Cells and Granulocyte/Macrophage Colony–stimulating Factor’ Journal of Experimental Medicine 188 (1) 133-143.