Interferon gamma-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)-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.
Zilocchi
C
C
Division of Experimental Oncology D, Istituto Nazionale per lo Studio e la Cura dei Tumori, 20133 Milan, Italy.
Stoppacciaro
A
A
Chiodoni
C
C
Parenza
M
M
Terrazzini
N
N
Colombo
M P
MP
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000032:analysis; D003110:Colonic Neoplasms / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000235:genetics / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007371:Interferon-gamma / Q000235:genetics*; D018664:Interleukin-12 / Q000235:genetics* / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000235:genetics; D009573:Nitrites / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism; D014407:Tumor Cells, Cultured
D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D009573:Nitrites; D018664:Interleukin-12; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor