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Biomaterials. 2014 Jul;35(21):5491-504. doi: 10.1016/j.biomaterials.2014.03.039. Epub 2014 Apr 8.

The effect of combined IL10 siRNA and CpG ODN as pathogen-mimicking microparticles on Th1/Th2 cytokine balance in dendritic cells and protective immunity against B cell lymphoma.

Author information

1
The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA.
2
Department of Lymphoma and Myeloma, The Center for Cancer Immunology Research, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
3
The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA. Electronic address: krish.roy@gatech.edu.

Abstract

Success of an immunotherapy for cancer often depends on the critical balance of T helper 1 (Th1) and T helper 2 (Th2) responses driven by antigen presenting cells, specifically dendritic cells (DCs). Th1-driven cytotoxic T cell (CTL) responses are key to eliminating tumor cells. It is well established that CpG oligonucleotides (ODN), a widely studied Toll-like receptor 9 (TLR9) agonist, used to enhance Th1 response, also induces high levels of the anti-inflammatory, Th2-promoting cytokine IL10, which could dampen the resulting Th1 response. Biomaterials-based immunomodulatory strategies that can reduce IL10 production while maintaining IL12 levels during CpG delivery could further enhance the Th1/Th2 cytokine balance and improve anti-tumor immune response. Here we report that dual-delivery of IL10-silencing siRNA along with CpG ODN to the same DCs using pathogen-mimicking microparticles (PMPs), significantly enhances their Th1/Th2 cytokine ratio through concurrent inhibition of CpG-induced IL10 production. Co-delivery of poly(I:C), a TLR3 agonist had only minor effects on IL10 levels. Further, simultaneous immunotherapy with CpG ODN and IL10 siRNA enhanced immune protection of an idiotype DNA vaccine in a prophylactic murine model of B cell lymphoma whereas co-delivery of poly(I:C) and CpG did not enhance protection. These results suggest that PMPs can be used to precisely modulate TLR ligand-mediated immune-stimulation in DCs, through co-delivery of cytokine-silencing siRNAs and thereby boost antitumor immunity.

KEYWORDS:

Cancer; CpG; Immunotherapy; Lymphoma; Microparticle; siRNA

[Indexed for MEDLINE]
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