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Both treated and untreated tumors are eliminated by short hairpin RNA-based induction of target-specific immune
Wenyi Gu1, Melanie Cochrane, Graham R Leggatt
1University of Queensland Diamantina Institute for Cancer, Royal Children's Hospital and Clinical Medical Virology Centre, University of Queensland, Brisbane, Australia.
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.
Insights
RNA interference (RNAi) cancer therapy can be enhanced by targeting cytotoxic T cell epitopes. This approach generates tumor-protective immunity, making some tumor cells resistant to direct RNAi treatment.
Area of Science:
- Immunology
- Molecular Biology
- Cancer Therapy
Background:
- RNA interference (RNAi) is a cancer treatment strategy that down-regulates target genes to kill cancer cells.
- Clinical adoption of RNAi is limited by delivery and efficacy issues.
- Existing research often uses immune-deficient models, neglecting adaptive immune system interactions.
Purpose of the Study:
- To investigate if RNA interference (RNAi) can trigger an immune response against cancer cells.
- To explore the potential for RNAi-generated truncated mRNAs to enhance immune presentation.
- To assess the therapeutic potential of RNAi-induced anti-tumor immunity.
Main Methods:
- Utilized short hairpin RNAs (shRNAs) to target specific genes in tumor cells.
- Analyzed the translation of RNAi-cleaved mRNAs into incomplete proteins.
- Assessed the presentation of target proteins and the generation of tumor-protective immune responses in mice.
- Investigated the impact of shRNA targeting location relative to cytotoxic T cell (CTL) epitopes.
Main Results:
- RNAi-cleaved mRNAs were translated into incomplete proteins.
- Targeting shRNAs downstream of CTL epitopes increased target protein presentation.
- This led to the generation of a tumor-protective immune response.
- Mice treated with shRNAs targeting CTL epitopes were protected from subsequent tumor challenges.
- Protection was dependent on shRNA targeting downstream of the dominant CTL epitope.
Conclusions:
- RNA interference can modulate the immune response to target genes.
- Not all tumor cells require direct RNAi exposure for effective in vivo treatment.
- This suggests a novel class of RNAi-based cancer therapies that leverage anti-tumor immunity.
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