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Differential Induction of Immunogenic Cell Death and Interferon Expression in Cancer Cells by Structured ssRNAs
Jaewoo Lee1, Youngju Lee1, Li Xu2
1Department of Surgery, Duke University, Durham, NC 27710, USA; Duke Translational Research Institute, Duke University, Durham, NC 27710, USA.
Abstract:
Activation of the RNA-sensing pattern recognition receptor (PRR) in cancer cells leads to cell death and cytokine expression. This cancer cell death releases tumor antigens and damage-associated molecular patterns (DAMPs) that induce anti-tumor immunity. However, these cytokines and DAMPs also cause adverse inflammatory and thrombotic complications that can limit the overall therapeutic benefits of PRR-targeting anti-cancer therapies. To overcome this problem, we generated and evaluated two novel and distinct ssRNA molecules (immunogenic cell-killing RNA [ICR]2 and ICR4). ICR2 and ICR4 differentially stimulated cell death and PRR signaling pathways and induced different patterns of cytokine expression in cancer and innate immune cells. Interestingly, DAMPs released from ICR2- and ICR4-treated cancer cells had distinct patterns of stimulation of innate immune receptors and coagulation. Finally, ICR2 and ICR4 inhibited in vivo tumor growth as effectively as poly(I:C). ICR2 and ICR4 are potential therapeutic agents that differentially induce cell death, immune stimulation, and coagulation when introduced into tumors.
Insights
Two novel RNA molecules, ICR2 and ICR4, effectively target cancer cells, inducing cell death and anti-tumor immunity while minimizing adverse effects. These immunogenic cell-killing RNAs show therapeutic potential for cancer treatment.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- RNA-sensing pattern recognition receptors (PRRs) in cancer cells trigger cell death and cytokine release, initiating anti-tumor immunity.
- However, PRR activation can also lead to detrimental inflammatory and thrombotic side effects, limiting therapeutic efficacy.
- Novel strategies are needed to harness PRR-mediated anti-cancer effects while mitigating adverse reactions.
Purpose of the Study:
- To develop and evaluate novel single-stranded RNA (ssRNA) molecules, ICR2 and ICR4, as potential anti-cancer therapeutics.
- To investigate the differential effects of ICR2 and ICR4 on cancer cell death, PRR signaling, cytokine expression, and immune activation.
- To assess the in vivo anti-tumor efficacy and coagulation effects of ICR2 and ICR4.
Main Methods:
- Generation and characterization of two distinct ssRNA molecules, ICR2 and ICR4.
- Assessment of cancer cell death and PRR pathway activation in response to ICR2 and ICR4.
- Analysis of cytokine profiles in cancer and immune cells treated with ICR2 and ICR4.
- Evaluation of damage-associated molecular patterns (DAMPs) released from treated cancer cells for innate immune receptor and coagulation stimulation.
- In vivo studies to determine tumor growth inhibition and coagulation effects of ICR2 and ICR4 compared to poly(I:C).
Main Results:
- ICR2 and ICR4 differentially modulated cancer cell death and PRR signaling pathways.
- Distinct cytokine expression patterns were observed in cancer and innate immune cells treated with ICR2 and ICR4.
- DAMPs released from ICR2- and ICR4-treated cells exhibited unique patterns of innate immune receptor and coagulation stimulation.
- Both ICR2 and ICR4 demonstrated significant in vivo tumor growth inhibition, comparable to poly(I:C).
Conclusions:
- ICR2 and ICR4 represent promising therapeutic agents for cancer treatment.
- These novel ssRNA molecules can differentially induce cancer cell death, immune stimulation, and coagulation.
- Further research into ICR2 and ICR4 may lead to improved PRR-targeting cancer therapies with a better safety profile.