Blocking the immunosuppressive axis with small interfering RNA targeting interleukin (IL)-10 receptor enhances dendritic cell-based vaccine potency

Kim, J. H.; Kang, Tae Heung; Noh, Kyung Hee; Bae, Hyun Cheol; Ahn, Yeong Hee; Lee, Y. H.; Choi, Eun Young; Chun, K. H.; Lee, S. J.; Kim, T. W.

doi:10.1111/j.1365-2249.2011.04410.x

Cited by 33 publications

(28 citation statements)

References 27 publications

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“…1b, vaccination with the BMDCs transfected with siRNAs targeting all the above immunosuppressive molecules led to an increase in the number of E7-specific CD8 1 T cell responses. Among all mice, those vaccinated with DCs transfected with siIL-10RA exhibited the highest frequency of E7-specific IFN-g 1 CD8 1 T cell precursors (628Á7 6 13Á5/3 3 10 5 splenocytes), and this finding was consistent with the result of our previous study [22]; a 12-fold increase compared to the number of T cells in mice that were vaccinated with the siGFPtransfected DCs (50Á9 6 14Á3/3 3 10 5 splenocytes) (P < 0Á0003). The next greatest increase in E7-specific IFN-g 1 CD8 1 T cell precursors was observed in mice vaccinated with siTGF-bR-transfected DCs (427Á7 6 17Á2/ 3 3 10 5 splenocytes), which enhanced the E7-specific CD8 1 T cell responses.…”

Section: Discussionsupporting

confidence: 91%

“…RNA interference (RNAi) technology is used widely to silence a variety of genes in vitro and in vivo due to its ability to specifically destroy the target mRNA. Our study and other studies have demonstrated successfully that silencing of endogenous enzymes, cytokines or receptors involved in DC apoptosis and immunosuppressive signalling improves antigen-specific CD8 1 cytotoxic T lymphocyte (CTL) responses against a tumour antigen in vitro and in vivo [16][17][18][19][20][21][22]. We have demonstrated that the siRNA targeting Bcl-2-like protein 11 (BIM) or phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a potent immunoadjuvant siRNA for DCbased vaccines, considering its ability to generate antigenspecific CD8 1 T cell immune responses.…”

Section: Introductionmentioning

confidence: 99%

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The siRNA cocktail targeting interleukin 10 receptor and transforming growth factor-β receptor on dendritic cells potentiates tumour antigen-specific CD8+ T cell immunity

Ahn

Hong

Kim

et al. 2015

Clinical and Experimental Immunology

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SummaryDendritic cells (DCs) are promising therapeutic agents in the field of cancer immunotherapy due to their intrinsic immune-priming capacity. The potency of DCs, however, is readily attenuated immediately after their administration in patients as tumours and various immune cells, including DCs, produce various immunosuppressive factors such as interleukin (IL)-10 and transforming growth factor (TGF)-b that hamper the function of DCs. In this study, we used small interfering RNA (siRNA) to silence the expression of endogenous molecules in DCs, which can sense immunosuppressive factors. Among the siRNAs targeting various immunosuppressive molecules, we observed that DCs transfected with siRNA targeting IL-10 receptor alpha (siIL-10RA) initiated the strongest antigen-specific CD8 1 T cell immune responses. The potency of siIL-10RA was enhanced further by combining it with siRNA targeting TGF-b receptor (siTGF-bR), which was the next best option during the screening of this study, or the previously selected immunoadjuvant siRNA targeting phosphatase and tensin homologue deleted on chromosome 10 (PTEN) or Bcl-2-like protein 11 (BIM). In the midst of sorting out the siRNA cocktails, the cocktail of siIL-10RA and siTGF-bR generated the strongest antigen-specific CD8 1 T cell immunity. Concordantly, the knock-down of both IL-10RA and TGF-bR in DCs induced the strongest anti-tumour effects in the TC-1 P0 tumour model, a cervical cancer model expressing the human papillomavirus (HPV)-16 E7 antigen, and even in the immune-resistant TC-1 (P3) tumour model that secretes more IL-10 and TGF-b than the parental tumour cells (TC-1 P0). These results provide the groundwork for future clinical development of the siRNA cocktail-mediated strategy by co-targeting immunosuppressive molecules to enhance the potency of DC-based vaccines.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

The siRNA cocktail targeting interleukin 10 receptor and transforming growth factor-β receptor on dendritic cells potentiates tumour antigen-specific CD8+ T cell immunity

Ahn

Hong

Kim

et al. 2015

Clinical and Experimental Immunology

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“…Depletion of Foxo3, a critical suppressive regulator of T cell proliferation, by RNAi increased the efficacy of a HER-2/neu DNA cancer vaccine (Wang et al, 2011c). Similarly knockdown of the IL10 receptor enhanced the potency of a DC vaccine (Kim et al, 2011). Furthermore, blockade of the programmed cell death-1 (PD-1) ligand B7-H1 (PD-L1) by RNAi augmented DC-mediated T cell responses and antiviral immunity in HBV transgenic mice (Jiang, 2012).…”

Section: Rnai Technologies In Dna Vaccine Designmentioning

confidence: 99%

The future of human DNA vaccines

Saade

Petrovsky

2012

Journal of Biotechnology

171

124

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DNA vaccines have evolved greatly over the last 20 years since their invention, but have yet to become a competitive alternative to conventional protein or carbohydrate based human vaccines. Whilst safety concerns were an initial barrier, the Achilles heel of DNA vaccines remains their poor immunogenicity when compared to protein vaccines. A wide variety of strategies have been developed to optimize DNA vaccine immunogenicity, including codon optimization, genetic adjuvants, electroporation and sophisticated prime-boost regimens, with each of these methods having its advantages and limitations. Whilst each of these methods has contributed to incremental improvements in DNA vaccine efficacy, more is still needed if human DNA vaccines are to succeed commercially. This review foresees a final breakthrough in human DNA vaccines will come from application of the latest cutting-edge technologies, including “epigenetics” and “omics” approaches, alongside traditional techniques to improve immunogenicity such as adjuvants and electroporation, thereby overcoming the current limitations of DNA vaccines in humans

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“…Similarly, depletion by RNAi of Foxo3, a critical suppressive regulator of T cell proliferation, increased the efficacy of a HER-2/neu cancer vaccine [114]. Knockdown of the IL10 receptor was also shown to enhance vaccine potency [115]. Furthermore, blockade of the PD-1 ligand (PD-L1) by RNAi augmented DC-mediated T cell responses and antiviral immunity in HBV transgenic mice [116].…”

Section: Shrna or Sirna As Molecular Adjuvantsmentioning

confidence: 99%

Molecular mechanisms for enhanced DNA vaccine immunogenicity

Petrovsky

2015

Expert Review of Vaccines

269

252

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Summary In the two decades since their initial discovery, DNA vaccines technologies have come a long way. Unfortunately, when applied to human subjects inadequate immunogenicity is still the biggest challenge for practical DNA vaccine use. Many different strategies have been tested in preclinical models to address this problem, including novel plasmid vectors and codon optimization to enhance antigen expression, new gene transfection systems or electroporation to increase delivery efficiency, protein or live virus vector boosting regimens to maximise immune stimulation, and formulation of DNA vaccines with traditional or molecular adjuvants. Better understanding of the mechanisms of action of DNA vaccines has also enabled better use of the intrinsic host response to DNA to improve vaccine immunogenicity. This review summarizes recent advances in DNA vaccine technologies and related intracellular events and how these might impact on future directions of DNA vaccine development.

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Blocking the immunosuppressive axis with small interfering RNA targeting interleukin (IL)-10 receptor enhances dendritic cell-based vaccine potency

Cited by 33 publications

References 27 publications

The siRNA cocktail targeting interleukin 10 receptor and transforming growth factor-β receptor on dendritic cells potentiates tumour antigen-specific CD8+ T cell immunity

The siRNA cocktail targeting interleukin 10 receptor and transforming growth factor-β receptor on dendritic cells potentiates tumour antigen-specific CD8+ T cell immunity

The future of human DNA vaccines

Molecular mechanisms for enhanced DNA vaccine immunogenicity

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