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J. Exp. Med., Volume 188, Number 1, July 1, 1998 133-143

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

By Chiara Zilocchi,* Antonella Stoppacciaro,Dagger Claudia Chiodoni,* Mariella Parenza,* Nadia Terrazzini,* and Mario P. Colombo*

From the * Division of Experimental Oncology D, Istituto Nazionale per lo Studio e la Cura dei Tumori, 20133 Milan, Italy; and the Dagger  Department of Experimental Medicine and Pathology, Second Chair of Pathology, University of Rome "La Sapienza", 00100 Rome, Italy

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 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 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 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-gamma in maintaining the CD8-polymorphonuclear leukocyte cross-talk that is a hallmark of tumor rejection.

Key words: interleukin 12;  tumor immunity;  knockout mice;  interferon gamma ;  CD4 T lymphocytes


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