Stat1 deficiency in the host enhances interleukin-12-mediated tumor regression.
Signal transducer and activator of transcription 1 (Stat1) is considered a key transcription factor that inhibits tumorigenesis, and Stat1 activation in the host is required for interleukin-12 (IL-12)-mediated generation of CTL activity. Using syngeneic Stat1-/- C3H mice bearing SCCVII tumors in this study, we discovered opposite results. Stat1 deficiency in the host significantly enhances IL-12-mediated tumor regression, resulting in tumor eradication from 60% of SCCVII tumor-bearing mice and significant inhibition of tumor growth when compared with control treatment (P < 0.01). This effect is independent of both Stat1-activating cytokine IFN-gamma and Stat1-downstream effector molecule FasL because neither neutralization of IFN-gamma nor knocking out of FasL enhances or inhibits IL-12-mediated tumor regression. IL-12 induces a high intensity of tumor-specific CTL activity in Stat1-deficient mice (P < 0.01), increases the CD8 T-cell density in tumor bearing Stat1-/- mice, and induces a T-cell-dependent tumor regression. The increased CTL activity and the high-intensity infiltration of T cells into the tumors in IL-12-treated Stat1-/- mice are likely due to the longer survival than the same cells from wild-type mice. Together, the data show that inhibition of Stat1 expression in the host enhances tumor-local IL-12 gene therapy for regressing tumors. This conclusion provides a new concept for designing an effective treatment strategy.
Torrero
Marina N
MN
Department of Comparative Biomedical Sciences, Louisiana State University, Baton Rouge, Louisiana 70803, USA.
Xia
Xueqing
X
Henk
Williams
W
Yu
Shry
S
Li
Shulin
S
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D053222:Fas Ligand Protein; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D018664:Interleukin-12 / Q000235:genetics* / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D050794:STAT1 Transcription Factor / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014162:Transfection; D048069:Tumor Necrosis Factors / Q000172:deficiency / Q000235:genetics / Q000276:immunology
D000906:Antibodies; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D048069:Tumor Necrosis Factors; D018664:Interleukin-12; D007371:Interferon-gamma