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Induction of tumour immunity by targeted inhibition of nonsense-mediated mRNA decay

Abstract

The main reason why tumours are not controlled by the immune system is that, unlike pathogens, they do not express potent tumour rejection antigens (TRAs). Tumour vaccination aims at stimulating a systemic immune response targeted to, mostly weak, antigens expressed in the disseminated tumour lesions. Main challenges in developing effective vaccination protocols are the identification of potent and broadly expressed TRAs1,2,3 and effective adjuvants to stimulate a robust and durable immune response4,5,6. Here we describe an alternative approach in which the expression of new, and thereby potent, antigens are induced in tumour cells by inhibiting nonsense-mediated messenger RNA decay (NMD)7,8,9,10. Small interfering RNA (siRNA)-mediated inhibition of NMD in tumour cells led to the expression of new antigenic determinants and their immune-mediated rejection. In subcutaneous and metastatic tumour models, tumour-targeted delivery of NMD factor-specific siRNAs conjugated to oligonucleotide aptamer ligands led to significant inhibition of tumour growth that was superior to that of vaccination with granulocyte–macrophage colony-stimulating factor (GM-CSF)-expressing irradiated tumour cells11, and could be further enhanced by co-stimulation. Tumour-targeted NMD inhibition forms the basis of a simple, broadly useful, and clinically feasible approach to enhance the antigenicity of disseminated tumours leading to their immune recognition and rejection. The cell-free chemically synthesized oligonucleotide backbone of aptamer–siRNAs reduces the risk of immunogenicity and enhances the feasibility of generating reagents suitable for clinical use.

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Figure 1: Expression of Upf2 or Smg1 shRNA in CT26 tumour cells leads to immune-mediated inhibition of tumour growth.
Figure 2: Inhibition of tumour growth in mice treated with PSMA aptamer targeted Upf2 and Smg1 siRNAs.
Figure 3: PSMA aptamer– Smg1 siRNA rejection of PSMA-expressing, but not parental, CT26 tumour cells.
Figure 4: Comparison of PSMA aptamer– Smg1 siRNA treatment to vaccination with GM-CSF expressing irradiated tumour cells.

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Acknowledgements

We thank J. Zhang for assistance in the mouse studies, A.-M. Jegg for technical assistance in characterizing Smg1 siRNAs, J. Rossi for advising in the design of aptamer–siRNA conjugates, and S. Nair and D. Boczkowski for advice in performing T-cell assays. This work was supported by the Dodson foundation and the Sylvester Comprehensive Cancer Center (Medical School, University of Miami).

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Contributions

F.P. suggested the approach and was responsible for designing the aptamer–siRNA conjugates and interpreting the results, D.K. was responsible for the mouse studies, P.H.G. helped design the aptamer–siRNA conjugates, and E.G. oversaw experimental design, data analysis, and wrote the manuscript.

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Correspondence to Eli Gilboa.

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The authors declare no competing financial interests.

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Pastor, F., Kolonias, D., Giangrande, P. et al. Induction of tumour immunity by targeted inhibition of nonsense-mediated mRNA decay. Nature 465, 227–230 (2010). https://doi.org/10.1038/nature08999

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