Both treated and untreated tumors are eliminated by short hairpin RNA-based induction of target-specific immune responses

Gu, Wenyi, Cochrane, Melanie, Leggatt, Graham, Payne, Elizabeth, Choyce, Allison, Zhou, Fang, Tindle, Robert and McMillan, Nigel (2009) Both treated and untreated tumors are eliminated by short hairpin RNA-based induction of target-specific immune responses. Proceedings of the National Academy of Sciences of the United States of America, 106 20: 8314-8319. doi:10.1073/pnas.0812085106


Author Gu, Wenyi
Cochrane, Melanie
Leggatt, Graham
Payne, Elizabeth
Choyce, Allison
Zhou, Fang
Tindle, Robert
McMillan, Nigel
Title Both treated and untreated tumors are eliminated by short hairpin RNA-based induction of target-specific immune responses
Journal name Proceedings of the National Academy of Sciences of the United States of America   Check publisher's open access policy
ISSN 0027-8424
1091-6490
Publication date 2009-05-19
Year available 2009
Sub-type Article (original research)
DOI 10.1073/pnas.0812085106
Open Access Status Not Open Access
Volume 106
Issue 20
Start page 8314
End page 8319
Total pages 6
Place of publication Washington, DC, United States
Publisher National Academy of Sciences
Language eng
Abstract RNA interference (RNAi) for cancer treatment relies on the ability to directly kill cancer cells via down-regulation of target genes, but issues of delivery and efficacy have limited clinical adoption. Furthermore, current studies using immune-deficient animal models disregard potential interactions with the adaptive immune system. It has previously been observed that certain viral antigens appear to be more rapidly presented to the immune system than normal proteins due to the production of defective ribosomal products by the virus. Given that RNAi could potentially result in the generation of truncated mRNAs, we wondered whether a similar mechanism of immune presentation of a target gene was possible. Here we show that RNAi-cleaved mRNAs can be translated into incomplete protein, and if cleavage was downstream of cytotoxic T cell epitopes, resulted in increased presentation of target protein and the generation of a tumor-protective immune response. We show that mice inoculated with tumor cells treated with such short hairpin RNAs (shRNAs) were protected from subsequent challenge with untreated tumors. However, protection was only found if shRNAs were targeted downstream of the dominant cytotoxic T cell (CTL) epitope. Our work suggests that RNAi can alter immunity to targets and shows that not all tumor cells require direct RNAi exposure for treatment to be effective in vivo, pointing the way to a new class of RNAi-based therapy.
Keyword Antigen presentation
CTL epitope
RNAi
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

 
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Created: Thu, 03 Sep 2009, 18:05:56 EST by Mr Andrew Martlew on behalf of UQ Diamantina Institute