Abstract
Over the past decade, immunotherapy has emerged as a promising new form of cancer treatment with the potential to eradicate tumor metastasis. However, its curative potential is in general limited by the existence of negative feedback mechanisms that control dendritic cells (DCs) and T-cell activation. For clinically effective immunity, there is a need of inhibiting the expression of these immune suppressors. This could enhance the activation of DCs, T cells, and natural killer cells, and might be beneficial for cancer immunotherapy. Among the immune inhibitory molecules expressed by DCs is indoleamine 2,3-dioxygenase (IDO), an enzyme that conveys immunosuppressive effects by degrading tryptophan, an essential amino acid required for T-cell proliferation and survival. Depletion of tryptophan by IDO-positive DCs induces T-cell apoptosis and the conversion of naïve CD4+ T cells into regulatory T cells that further suppress antitumor immunity. Herein, we describe a protocol for in vitro synthesis of small interfering RNA against IDO and other immunosuppressive factors such as interleukin-10 and programmed cell death-1 ligands in order to reverse immune suppression mediated by DCs. Vaccination with IDO-silenced DC vaccines enhanced immune responses and antitumor immunity in cancer patients.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Steinman RM, Banchereau J (2007) Taking dendritic cells into medicine. Nature 449:245–252
Hoos A, Britten CM, Huber C, O’Donnell-Tormey J (2011) A methodological framework to enhance the clinical success of cancer immunotherapy. Nat Biotechnol 29:867–870
Munn DH, Sharma MD, Lee JR, Jhaver KG, Johnson TS et al (2002) Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase. Science 297:1867–1870
Hwu P, Du MX, Lapointe R, Do M, Taylor M-W, Young HA (2000) Indoleamine 2,3-dioxygenase production by human dendritic cells results in the inhibition of T cell proliferation. J Immunol 164:3596–3599
Braun D, Longman RS, Albert ML (2005) A two-step induction of indoleamine 2,3 dioxygenase (IDO) activity during dendritic cell maturation. Blood 106:2375–2381
Munn DH, Sharma MD, Hou D (2004) Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in draining-draining lymph nodes. J Clin Invest 114:280–290
Jonuleit H, Schmitt E, Stenbrink K, Enk AH (2001) Dendritic cells as a tool to induce anergic and regulatory T cells. Trends Immunol 22:394–400
Flatekval GF, Sioud M (2009) Modulation of dendritic cell function and maturation with mono- and bifunctional small interfering RNAs targeting indoleamine 2,3-dioxygenase. Immunology 128:e837–e848
Sioud M, Saebøe-Larssen S, Hetland TE, Kaern J, Mobergslien A, Kvalheim G (2013) Silencing of indoleamine 2,3-dioxygenase enhances dendritic cell immunogenicity and antitumour immunity in cancer patients. Int J Oncol 43:280–288
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2015 Springer Science+Business Media New York
About this protocol
Cite this protocol
Sioud, M., Mobergslien, A., Sæbøe-Larssen, S. (2015). Immunosuppressive Factor Blockade in Dendritic Cells via siRNAs Results in Objective Clinical Responses. In: Sioud, M. (eds) RNA Interference. Methods in Molecular Biology, vol 1218. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-1538-5_16
Download citation
DOI: https://doi.org/10.1007/978-1-4939-1538-5_16
Published:
Publisher Name: Humana Press, New York, NY
Print ISBN: 978-1-4939-1537-8
Online ISBN: 978-1-4939-1538-5
eBook Packages: Springer Protocols