Editors' ChoiceCancer

The Trojan Horse for Hematologic Malignancies

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Science Translational Medicine  23 Jan 2013:
Vol. 5, Issue 169, pp. 169ec17
DOI: 10.1126/scitranslmed.3005694

Signal transducer and activator of transcription 3 (STAT3), a transcription factor present in both malignant and nonmalignant tumor–associated cells, is critical for the survival of many types of blood cancers. Development of a STAT3-specific inhibitor is a promising therapeutic approach for the treatment of hematologic malignancies but has been difficult to achieve so far. A recently reported strategy promises to overcome these difficulties by targeting Toll-like receptor 9 (TLR9), a pathogen-recognition receptor found on immune cells, for cell-specific delivery of small interfering RNA (siRNA) against STAT3. To do this, the authors coupled their siRNA with CpG oligonucleotides, the natural ligand of TLR9, producing conjugates called CpG(A)-STAT3 and CpG(B)-STAT3 siRNA (the A type normally stimulates interferon production, whereas the B type activates B cells).

Zhang et al. demonstrated in a mouse model of B cell lymphoma that CpG(B)-STAT3 siRNA treatment combined with local radiotherapy can prevent the growth of TLR9-positive lymphomas and provide long-term protective immunity against the primary cancer. They also showed that human cell–specific CpG(A)-STAT3 siRNA was quickly and efficiently internalized by cultured dendritic cells and primary B cells, but not by monocytes, which express almost undetectable levels of TLR9. Once inside the cells, the siRNA activated TLR9 and reduced STAT3 expression, without any evidence of toxic side effects. The inhibition of STAT3 mRNA expression, however, was transient and faded after prolonged cell culture. In vivo experiments in immunodeficient mice bearing subcutaneous grafts of TLR9-positive human leukemia showed that CpG(A)-STAT3­ siRNA reduced STAT3 protein expression and was directly cytotoxic to the tumors. CpG(A)-siRNA targeting BCL-XL (another protein that promotes tumor survival) had a similar effect. Aside from its tumoricidal effects, CpG(A)-STAT3 siRNA also activated plasmacytoid dendritic cells and increased tumor infiltration by innate immune cells such as neutrophils, which could contribute to the overall antitumor effect.

In summary, Zhang and coauthors developed a promising method of using RNA interference to decrease the survival of TLR9-positive cancer cells by attacking them from within, while simultaneously activating human dendritic cells in the tumor microenvironment to restore antitumor immunity. Further studies are needed to optimize the serum stability and circulatory half-life of the new siRNA conjugates before this Trojan horse approach can be used to treat hematologic malignancies.

Q. Zhang et al., TLR9-mediated siRNA delivery for targeting of normal and malignant human hematopoietic cells in vivo. Blood, published online 3 January 2013 (10.1182/blood-2012-07-442590). [Abstract]

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