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.
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.
The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA.
Pallab
P
Pradhan
Department of Lymphoma and Myeloma, The Center for Cancer Immunology Research, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Hong
H
Qin
The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA.
Jardin A
JA
Leleux
Department of Lymphoma and Myeloma, The Center for Cancer Immunology Research, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Dongho
D
Gwak
Department of Lymphoma and Myeloma, The Center for Cancer Immunology Research, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Ippei
I
Sakamaki
Department of Lymphoma and Myeloma, The Center for Cancer Immunology Research, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Larry W
LW
Kwak
The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA. Electronic address: krish.roy@gatech.edu.
Krishnendu
K
Roy
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D032701:Biomimetics / Q000379:methods; D055252:Cell-Derived Microparticles / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D007167:Immunotherapy / Q000379:methods; D016753:Interleukin-10 / Q000276:immunology*; D016393:Lymphoma, B-Cell / Q000276:immunology*; D059630:Mesenchymal Stem Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000494:pharmacology*; D011070:Poly I-C / Q000737:chemistry / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D058408:Th1-Th2 Balance; D051196:Toll-Like Receptor 3 / Q000819:agonists / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000378:metabolism
D000970:Antineoplastic Agents; C408982:CPG-oligonucleotide; D009838:Oligodeoxyribonucleotides; D034741:RNA, Small Interfering; C519703:TLR3 protein, mouse; C495370:Tlr9 protein, mouse; D051196:Toll-Like Receptor 3; D051217:Toll-Like Receptor 9; D016753:Interleukin-10; D011070:Poly I-C
Cancer; CpG; Immunotherapy; Lymphoma; Microparticle; siRNA