Transfection of the genes for interleukin-12 into the K1735 melanoma and the EMT6 mammary sarcoma murine cell lines reveals distinct mechanisms of antitumor activity.
Interleukin 12 (IL-12) is a pleiotropic cytokine with multiple effects on the immune system. The antitumor effects of locally produced IL-12 were examined in 2 tumor model systems. IL-12 expressing EMT6 mammary sarcomas (EMT6/IL-12) grew temporarily and then regressed resulting in mice that were immune to a further challenge of EMT6 cells. Interestingly, the IL-12 expressing K1735 melanomas (K1735/IL-12) maintained a lag phase of nonmeasurable growth for several weeks, followed by tumor outgrowth that was associated with a loss of IL-12 production. Tumor-infiltrating lymphocytes (TILs) isolated from EMT6/IL-12 tumors effectively lysed EMT6 target cells, whereas K1735/IL-12 TILs lacked lytic activity. Both IL-12 expressing tumors, however, grew progressively in nude mice indicating an important role for T cells in each case. Recombinant murine interferon gamma (rmIFN-gamma) inhibited the growth of EMT6 cells, but not K1735 cells in vitro, and strongly induced the expression of the antiangiogenic chemokine interferon-inducible protein 10 (IP-10) by both cell lines. Of interest, only the EMT6 cell line was able to secrete the proangiogenic molecule, vascular endothelial growth factor (VEGF), in response to low oxygen conditions. Fluorescent staining of the vascular endothelium at the tumor injection site provided images depicting early stages of angiogenesis prior to K1735/IL-12 tumor outgrowth. These results indicate that locally produced IL-12 likely mediates the rejection of EMT6 tumors through tumor cell lysis by host immune cells, whereas its antiangiogenic potential may be counterbalanced by the strong induction of VEGF by hypoxic tumor cells. In contrast, IL-12 does not induce protective immunity to K1735 tumors. However, an antiangiogenic mechanism may be responsible for controlling tumor growth.
Moran
James P
JP
Department of Microbiology and Immunology and James P. Wilmot Cancer Center, University of Rochester, Rochester, NY, USA.
Gerber
Scott A
SA
Martin
Celeste A
CA
Frelinger
John G
JG
Lord
Edith M
EM
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D054357:Chemokine CXCL10 / Q000378:metabolism; D016228:Endothelial Growth Factors / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D018664:Interleukin-12 / Q000235:genetics* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008222:Lymphokines / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology*; D008546:Melanoma, Experimental / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008819:Mice, Nude; D010100:Oxygen / Q000378:metabolism; D010957:Plasmids; D011994:Recombinant Proteins / Q000378:metabolism; D012513:Sarcoma, Experimental / Q000378:metabolism / Q000473:pathology*; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D054357:Chemokine CXCL10; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D018664:Interleukin-12; D007371:Interferon-gamma; D010100:Oxygen