| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
-Induced Janus Kinase-STAT Signaling and Potentiate the Antitumor Effects of IFN- in a Murine Model of Malignant Melanoma1
,
* Departments of Human Cancer Genetics,
Surgery and
Medical Microbiology, Virology and Immunology, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Ohio State University, Columbus, OH 43210; and
Primetrics, Inc., Hilliard, OH 43026
IFN-
2b (IFN-) has been used to treat patients with metastatic malignant melanoma and patients rendered disease-free via surgery but at high risk for recurrence. We hypothesized that IL-12 pretreatments would result in endogenous IFN-
production, and that this, in turn, would up-regulate levels of Janus kinase-STAT signaling intermediates and lead to increased expression of genes regulated by IFN-. Treatment of PBMCs with IL-12 stimulated a significant and dose-dependent production of IFN-. Pretreatment of PBMCs and tumor cells with IFN--containing supernatants from IL-12-stimulated PBMCs led to up-regulation of STAT1, STAT2, and IFN regulatory factor 9 (IRF9) and potentiated IFN--induced STAT signaling within PBMCs and tumor cells. These effects were abrogated by neutralization of IFN- in the PBMC supernatants with an anti-IFN- Ab. Pretreatment of HT144 melanoma cells and PBMCs with IFN- or IFN--containing supernatants enhanced the actions of IFN- at the transcriptional level, as measured by real-time RT PCR analysis of the IFN-stimulated gene 15. Experiments in wild-type C57BL/6 and IFN- receptor knockout (B6.129S7-Ifngrtm1Agt) mice demonstrated that a regimen of IL-12 pretreatment, followed by IFN-, could cure mice of i.p. B16F1 melanoma tumors (p < 0.007), whereas mice treated with either agent alone or PBS succumbed to fatal tumor burden. However, this treatment regimen did not significantly prolong the survival of IFN--deficient (B6.129S7-Ifngtm1Ts) mice compared with mice treated with IFN- alone. These results suggest that the response to IFN- immunotherapy can be significantly enhanced by IL-12 pretreatment, and this effect is dependent upon endogenous IFN- production and its actions on melanoma cells.
This article has been cited by other articles:
|
|
 |
|
  G. B. Lesinski, J. Trefry, M. Brasdovich, S. V. Kondadasula, K. Sackey, J. M. Zimmerer, A. R. Chaudhury, L. Yu, X. Zhang, T. R. Crespin, et al. Melanoma Cells Exhibit Variable Signal Transducer and Activator of Transcription 1 Phosphorylation and a Reduced Response to IFN-{alpha} Compared with Immune Effector Cells Clin. Cancer Res., September 1, 2007; 13(17): 5010 - 5019. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Zimmerer, G. B. Lesinski, S. V. Kondadasula, V. I. Karpa, A. Lehman, A. RayChaudhury, B. Becknell, and W. E. Carson III IFN-{alpha}-Induced Signal Transduction, Gene Expression, and Antitumor Activity of Immune Effector Cells Are Negatively Regulated by Suppressor of Cytokine Signaling Proteins J. Immunol., April 15, 2007; 178(8): 4832 - 4845. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. F. Eisenbeis, G. B. Lesinski, M. Anghelina, R. Parihar, D. Valentino, J. Liu, P. Nadella, P. Sundaram, D. C. Young, M. Sznol, et al. Phase I Study of the Sequential Combination of Interleukin-12 and Interferon Alfa-2b in Advanced Cancer: Evidence for Modulation of Interferon Signaling Pathways by Interleukin-12 J. Clin. Oncol., December 1, 2005; 23(34): 8835 - 8844. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Craft, K. W. Bruhn, B. D. Nguyen, R. Prins, J. W. Lin, L. M. Liau, and J. F. Miller The TLR7 Agonist Imiquimod Enhances the Anti-Melanoma Effects of a Recombinant Listeria monocytogenes Vaccine J. Immunol., August 1, 2005; 175(3): 1983 - 1990. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
