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| FIBROBLASTS GENETICALLY-ENGINEERED TO SECRETE INTERLEUKIN-12 CAN SUPPRESS TUMOR-GROWTH AND INDUCE ANTITUMOR IMMUNITY TO A MURINE MELANOMA IN-VIVO |
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| Author(s): TAHARA H, ZEH HJ, STORKUS WJ, PAPPO I, WATKINS SC, GUBLER U, WOLF SF, ROBBINS PD, LOTZE MT |
| Source: CANCER RESEARCH Volume: 54 Issue: 1 Pages: 182-189 Published: JAN 1 1994 |
| Times Cited: 305 References: 36 |
| Abstract: Interleukin 12 (IL-12), a disulfide-linked heterodimeric cytokine produced primarily by macrophages, is composed of light (p35) and heavy (p40) chains. It binds to a receptor on T-cells and natural killer cells, promoting the induction of primarily a T(H)1 response in vitro and in vivo. To determine whether paracrine IL-12 secretion can alter tumor cell growth or promote antitumor immunity, we have developed a delivery system using genetically engineered fibroblasts in murine tumor models. NIH3T3 cells were stably transfected to express 100-240 units/10(6) cells/48 h of IL-12 using expression plasmids carrying both the murine p35 and p40 genes of murine IL-12. The effects of paracrine secretion of IL-12 on tumor establishment and vaccination models were examined using the poorly immunogenic murine melanoma cell line (BL-6) in C57BL/6 mice. To determine the effects of IL-12 on tumor formation, nonirradiated BL-6 cells were inoculated s.c. into C57BL/6 mice admixed with NIH3T3 cells transfected with both subunits of mIL-12 (3T3-IL-12) or with cells transfected with only the neomycin phosphotransferase gene (3T3-Neo). Compared to mice given injections of BL-6 alone, the day of emergence of detectable tumors was significantly delayed in mice given injections of BL-6 admixed with 3T3-IL-12, but not in mice with BL-6 admixed with 3T3-Neo. Effectiveness in this system was related to the amount of IL-12 expressed by the 3T3-IL-12. To determine the ability of locally secreted IL-12 at the tumor site to induce antitumor immunity, 10(6) irradiated tumor cells mixed with 3T3-IL-12 or 3T3-Neo were injected as a vaccine, and the response to a tumor challenge was subsequently examined. With a tumor challenge of less than 1 x 10(5) nonirradiated BL-6 cells, significant delay of establishment of tumor was noted with a relatively small amount of IL-12 secretion (1.2 units/5 x 10(5) cells/48 h). Larger amounts of secreted IL-12 provided no additional therapeutic benefit. Histological examination of tumor inoculum with 3T3-IL-12 secreting a high level of IL-12 showed peritumoral accumulation of macrophages, a characteristic capsule around the tumor composed of palisades of fibroblasts, and decreased numbers of CD4+ cells in the tumor. These results suggest that local delivery of IL-12 inhibits tumor growth in a dose dependent manner but leads to the development of an antitumor immune response when IL-12 is expressed at the tumor site at the relatively small amount indicated above. These results suggest that IL-12, like IL-2, -4, -6, and -7 and granulocyte-macrophage colony-stimulating factor, can induce an immune response against poorly immunogenic tumors. |
| Document Type: Article |
| Language: English |
Addresses:
1. UNIV PITTSBURGH, SCH MED, DEPT SURG, ONCOL SURG SECT, W1543 BIOMED SCI TOWER, PITTSBURGH, PA 15261 USA
2. UNIV PITTSBURGH, SCH MED, DEPT MOLEC GENET & BIOCHEM, PITTSBURGH, PA 15261 USA
3. GENET INST INC, CAMBRIDGE, MA USA
4. UNIV PITTSBURGH, SCH MED, DEPT CELL BIOL & PHYSIOL, PITTSBURGH, PA 15261 USA
5. HOFFMANN LA ROCHE INC, ROCHE RES CTR, DEPT INFLAMMAT AUTOIMMUNE DIS, NUTLEY, NJ 07110 USA |
| Publisher: AMER ASSOC CANCER RESEARCH, PUBLIC LEDGER BLDG, SUITE 816, 150 S. INDEPENDENCE MALL W., PHILADELPHIA, PA 19106 |
| Subject Category: Oncology |
| IDS Number: MQ280 |
| ISSN: 0008-5472 |
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