IL-12- and IL-2-induced tumor regression in a new murine model of oral squamous-cell carcinoma is promoted by expression of the CD80 co-stimulatory molecule and interferon-gamma.
Therapy with IL-12 or IL-2 induces tumor regression in only a few patients with head-and-neck squamous cell carcinoma (SCC), and the factors promoting responsiveness have not been well defined. In this study, we examined whether combined IL-12 and IL-2 therapy can induce tumor regression in a new murine model of oral SCC and determined if the anti-tumor response is promoted by expression of the immune co-stimulatory molecule CD80 and cytokine IFN-gamma. In CD80-positive or -negative subclones of a BALB/c oral SCC line in syngeneic mice, we showed that systemic rIL-12 alone was comparable in effectiveness to combined therapy with IL-12 and peri-tumoral rIL-2, inducing complete regression of the CD80(+) line B7E11-4scid. However, therapy with these cytokines had no effect on growth of the CD80(-) subclone B7E3-4scid and did not induce complete regression of the CD80(+) subclone B7E11-4scid in congenic BALB/c IFN-gamma knockout mice, indicating that expression of the CD80 co-stimulatory molecule and IFN-gamma contributes to tumor regression. In cytokine-treated mice that rejected the CD80(+) SCC line, an increase in infiltrating CD4(+) lymphocytes and apoptotic bodies within the tumor specimens was observed, and resistance to rechallenge with the same tumor was detected in 50% of recipients, consistent with an immune response. Our results provide evidence that regression of oral head-and-neck SCC may be induced by therapy with systemic IL-12 and that expression of the CD80 co-stimulatory molecule by SCC and IFN-gamma by the host promote IL-12 induced regression of SCC.
Thomas
G R
GR
Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and other Communication Disorders, National Institutes of Health, Bethesda, MD 20892-1419, USA.
Chen
Z
Z
Enamorado
I
I
Bancroft
C
C
Van Waes
C
C
D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D018122:B7-1 Antigen / Q000096:biosynthesis / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics*; D018664:Interleukin-12 / Q000494:pharmacology / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use
D020533:Angiogenesis Inhibitors; D018122:B7-1 Antigen; D007376:Interleukin-2; D011994:Recombinant Proteins; D018664:Interleukin-12; D007371:Interferon-gamma