Induction of Tumor Immunity by Targeted Inhibition of Nonsense-mediated mRNA Decay

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

Whereas tumor progression in cancer patients can elicit a weak immune response which keeps the tumor in check, albeit transiently, the weak antigenicity of the tumor provides the time and opportunity for the tumor to elaborate immune evasion mechanisms. Weak antigenicity is, therefore, the root cause why tumors escape immune control. We have recently described a way to activate the antitumor immune response that is fundamentally different from current strategies collectively referred to as "cancer vaccination," because instead of stimulating immune responses against existing and mostly weak, tumor antigens, novel, and thereby potent, antigens are induced de novo in the disseminated tumor lesions of the patient. The approach is to inhibit a process in the tumor cells known as nonsense-mediated mRNA decay (NMD). The physiological role of NMD is to eliminate defective products generated in the cells, and therefore inhibiting the NMD process will lead to the accumulation of defective products, some of which will encode novel, and thereby potent, antigens to which the immune system has not been tolerized. Inhibition of NMD was accomplished using chemically synthesized siRNAs to downregulate key mediators of the NMD process such as Smg-1 or Upf-2. However, since NMD is a constitutive process that operates in all the somatic cells of the body, global inhibition of NMD could lead to system-wide autoimmune pathology. To obviate the risk of autoimmunity, NMD inhibition was limited to the disseminated tumor lesions by targeted delivery of siRNAs conjugated to oligonucleotide aptamer ligands that bind to receptors expressed preferentially, if not exclusively, on the tumor cells. We have shown that in subcutaneous and metastatic murine tumor models, the tumortargeted delivery of NMD factor siRNAs led to signifi cant inhibition of tumor growth which was superior to that of a gold standard "conventional" cancer vaccination protocol. Tumor-targeted NMD inhibition forms the basis of a simple, broadly useful, and clinically feasible approach to enhance the antigenicity of disseminated tumors leading to their immune recognition and rejection. The cellfree chemically synthesized oligonucleotide backbone of aptamer-siRNAs reduces the risk of immunogenicity and enhances the feasibility of generating reagents suitable for clinical use.

Original languageEnglish (US)
Title of host publicationAdvances in Tumor Immunology and Immunotherapy
PublisherSpringer New York
Pages67-82
Number of pages16
ISBN (Electronic)9781461488095
ISBN (Print)9781461488088
DOIs
StatePublished - Jan 1 2014

Fingerprint

Nonsense Mediated mRNA Decay
Immunity
Neoplasms
Oligonucleotides
Vaccination
Tumor Escape
Immune Evasion
Antigens

Keywords

  • Cancer immunotherapy
  • Nonsense-mediated mRNA decay
  • Oligonucleotide aptamers
  • Small interfering RNAs
  • Tumor antigens

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Gilboa, E. (2014). Induction of Tumor Immunity by Targeted Inhibition of Nonsense-mediated mRNA Decay. In Advances in Tumor Immunology and Immunotherapy (pp. 67-82). Springer New York. https://doi.org/10.1007/978-1-4614-8809-5_5

Induction of Tumor Immunity by Targeted Inhibition of Nonsense-mediated mRNA Decay. / Gilboa, Eli.

Advances in Tumor Immunology and Immunotherapy. Springer New York, 2014. p. 67-82.

Research output: Chapter in Book/Report/Conference proceedingChapter

Gilboa, E 2014, Induction of Tumor Immunity by Targeted Inhibition of Nonsense-mediated mRNA Decay. in Advances in Tumor Immunology and Immunotherapy. Springer New York, pp. 67-82. https://doi.org/10.1007/978-1-4614-8809-5_5
Gilboa E. Induction of Tumor Immunity by Targeted Inhibition of Nonsense-mediated mRNA Decay. In Advances in Tumor Immunology and Immunotherapy. Springer New York. 2014. p. 67-82 https://doi.org/10.1007/978-1-4614-8809-5_5
Gilboa, Eli. / Induction of Tumor Immunity by Targeted Inhibition of Nonsense-mediated mRNA Decay. Advances in Tumor Immunology and Immunotherapy. Springer New York, 2014. pp. 67-82
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