The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/7/133/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 1, July 1, 1998 133-143

Articles

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

Chiara Zilocchi*, Antonella Stoppacciaro{ddagger}, 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 {ddagger} 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

Address correspondence to Mario P. Colombo, Experimental Oncology D, Istituto Nazionale Tumori, Via Venezian 1, 20133 Milano, Italy. Phone: 39-2-2390-252; Fax: 39-2-2362-692; E-mail: mcolombo{at}istitutotumori.mi.it

Abbreviations used: CMC, cell-mediated cytotoxicity; GKO, IFN-{gamma} knockout mice; IP-10, IFN-inducible protein 10; MIG, monokine induced by {gamma}-IFN; PAP, peroxidase antiperoxidase.


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