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Surgery. 2006 Aug;140(2):297-306.

Interferon alpha and CPG oligodeoxynucleotides elicit additive immunostimulatory and antitumor effects.

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  • 1Department of Surgery, Human Cancer Genetics Program, Columbus, OH, USA.

Abstract

BACKGROUND:

We hypothesized that interferon alpha (IFN-alpha) and unmethylated cytosine-phosphothioate-guanine (CpG)-rich oligodexoynucleotides (CpG ODNs) would elicit potent antitumor activity due to the ability of this treatment combination to activate complimentary signal transduction intermediates.

METHODS:

Peripheral blood mononuclear cells treated with CpG ODNs, IFN-alpha, or both agents combined were evaluated for cytotoxicity against human melanoma cells, Jak-STAT signal transduction by flow cytometry, and ISG-15 gene expression by real-time polymerase chain reaction. The effects of CpG ODNs and IFN-alpha were evaluated in murine models of melanoma in wild-type, IFN-gamma-deficient, and STAT1-deficient mice. Negative controls in all experiments included treatment with control ODN or phosphate-buffered saline.

RESULTS:

Treatment of peripheral blood mononuclear cells with a combination of CpG ODNs and IFN-alpha resulted in enhanced cytotoxicity, activation of natural killer cells, IFN-alpha-induced STAT1 phosphorylation, and transcription levels of ISG-15. These immunostimulatory effects of CpG ODNs were associated with increased expression of STAT1 and STAT2 proteins. Administration of CpG ODNs plus IFN-alpha elicited superior antitumor activity in a murine model of B16 melanoma compared with either agent alone. The antitumor properties of CpG ODNs were dependent on STAT1-mediated signal transduction within the host but independent of endogenously produced IFN-gamma.

CONCLUSIONS:

CpG ODNs represent potent immune stimulants that elicit antitumor effects through STAT1-mediated signal transduction.

PMID:
16904983
[PubMed - indexed for MEDLINE]
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