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Updated: Mar 24, 2026
Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Immunogenic cell death by oncolytic herpes simplex virus type 1 in squamous cell carcinoma cells
A Takasu1, A Masui1, M Hamada1
1Department of Oral and Maxillofacial Surgery II, Osaka University Graduate School of Dentistry, Suita, Osaka, Japan.
Abstract:
Molecules essential for the induction of immunogenic cell death (ICD) are called damage-associated molecular patterns (DAMPs). The effects of oncolytic herpes simplex virus type 1 (HSV-1) on the production of DAMPs were examined in squamous cell carcinoma (SCC) cells. The cytopathic effects of HSV-1 RH2 were observed in mouse SCCVII cells infected at a high multiplicity of infection (MOI), and the amounts of viable cells were decreased. After being infected with RH2, ATP and high mobility group box 1 (HMGB1) were released extracellulary, while calreticulin (CRT) translocated to the cell membrane. A flow-cytometric analysis revealed an increase in the number of annexin-V and propidium iodide (PI)-stained cells; and the amount of cleaved poly (ADP-ribose) polymerase (PARP) was increased. The killing effect of RH2 was reduced by pan-caspase inhibitor z-VAD-fmk and the caspase-1 inhibitor z-YVAD-fmk, suggesting the involvement of apoptosis and pyroptosis. In C3H mice bearing synergic SCCVII tumors, the growth of tumors injected with the supernatant of RH2-infected cells was less than that of tumors injected with phosphate-buffered saline (PBS). These results indicate that oncolytic HSV-1 RH2 produces DAMPs from SCC cells to induce cell death. This may contribute to the enhancement of tumor immunity by oncolytic HSV-1.
Insights
Oncolytic herpes simplex virus type 1 (HSV-1) induces immunogenic cell death in cancer cells by releasing damage-associated molecular patterns (DAMPs). This process, involving apoptosis and pyroptosis, enhances anti-tumor immunity.
Area of Science:
- Oncology
- Virology
- Immunology
Background:
- Immunogenic cell death (ICD) is crucial for initiating anti-tumor immune responses.
- Damage-associated molecular patterns (DAMPs) are key mediators of ICD.
- Oncolytic viruses are engineered to selectively kill cancer cells and stimulate immunity.
Purpose of the Study:
- To investigate the effects of oncolytic herpes simplex virus type 1 (HSV-1) on DAMP production in squamous cell carcinoma (SCC) cells.
- To elucidate the mechanisms of cell death induced by HSV-1 in SCC.
- To assess the potential of HSV-1 in enhancing anti-tumor immunity.
Main Methods:
- Infection of mouse SCCVII cells with HSV-1 RH2 at a high multiplicity of infection (MOI).
- Measurement of extracellular ATP and HMGB1 release, and cell surface calreticulin (CRT) translocation.
- Flow cytometry analysis for annexin-V and propidium iodide (PI) staining, and Western blotting for cleaved PARP.
- Assessment of cell death pathways using pan-caspase and caspase-1 inhibitors.
- In vivo studies using C3H mice bearing SCCVII tumors to evaluate the anti-tumor effect of RH2-infected cell supernatant.
Main Results:
- HSV-1 RH2 infection led to decreased viable SCCVII cells and induced cytopathic effects.
- Extracellular release of ATP and HMGB1, and cell surface translocation of CRT were observed.
- Increased annexin-V and PI staining indicated apoptosis and necrosis, while elevated cleaved PARP suggested apoptosis.
- Inhibition of caspases reduced the killing effect, implicating apoptosis and pyroptosis.
- Tumor growth was suppressed in mice treated with supernatant from RH2-infected cells.
Conclusions:
- Oncolytic HSV-1 RH2 effectively induces DAMPs production and cell death in SCC cells.
- The cell death mechanisms involved apoptosis and pyroptosis, mediated by caspase activation.
- The release of DAMPs by HSV-1-infected SCC cells contributes to the suppression of tumor growth, potentially enhancing anti-tumor immunity.
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