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MicroRNA-based Regulation of Picornavirus Tropism
Published on: February 6, 2017
The Effect of Vector Silencing during Picornavirus Vaccination against Experimental Melanoma and Glioma
Courtney S Malo1,2, Danielle N Renner2,3, April M Huseby Kelcher1,2
1Department of Immunology, Mayo Clinic, Rochester, MN, United States of America.
Abstract:
Virus vector-based vaccination against tumor-specific antigens remains a promising therapeutic approach to overcome the immune suppressive tumor microenvironment. However, the extent that the desired CD8 T cell response against the targeted tumor antigen is impacted by the CD8 T cell response against the virus vector is unclear. To address this question, we used picornavirus vaccination with Theiler's murine encephalomyelitis virus (TMEV) as our vector against tumor-expressed ovalbumin (OVA257-264) antigen in both the B16-OVA murine melanoma and GL261-quad cassette murine glioma models. Prior to vaccination, we employed vector silencing to inhibit the CD8 T cell response against the immunodominant TMEV antigen, VP2121-130. We then monitored the resulting effect on the CD8 T cell response against the targeted tumor-specific antigen, ovalbumin. We demonstrate that employing vector silencing in the context of B16-OVA melanoma does not reduce tumor burden or improve survival, while TMEV-OVA vaccination without vector silencing controls tumor burden. Meanwhile, employing vector silencing during picornavirus vaccination against the GL261-quad cassette glioma resulted in a lower frequency of tumor antigen-specific CD8 T cells. The results of this study are relevant to antigen-specific immunotherapy, in that the virus vector-specific CD8 T cell response is not competing with tumor antigen-specific CD8 T cells. Furthermore, vector silencing may have the adverse consequence of reducing the tumor antigen-specific CD8 T cell response, as demonstrated by our findings in the GL261-quad cassette model.
Insights
Virus vector vaccination shows promise for cancer immunotherapy. Inhibiting the virus-specific CD8 T cell response did not improve melanoma outcomes but unexpectedly reduced anti-tumor T cells in glioma models, suggesting potential harm.
Area of Science:
- Immunology
- Oncology
- Virology
Background:
- Virus vectors are promising for cancer immunotherapy by targeting tumor antigens.
- The impact of CD8 T cell responses against the virus vector on anti-tumor immunity is not well understood.
Purpose of the Study:
- To investigate if inhibiting the CD8 T cell response against a virus vector affects anti-tumor CD8 T cell responses.
- To evaluate the therapeutic efficacy of vector silencing in combination with virus vector-based cancer vaccination.
Main Methods:
- Utilized Theiler's murine encephalomyelitis virus (TMEV) as a vector for ovalbumin (OVA) antigen delivery in B16-OVA melanoma and GL261-quad cassette glioma models.
- Employed vector silencing to suppress CD8 T cell responses against the immunodominant TMEV VP2121-130 antigen prior to vaccination.
- Monitored CD8 T cell responses against the tumor antigen (OVA) and assessed tumor burden and survival.
Main Results:
- In B16-OVA melanoma, vector silencing did not reduce tumor burden or improve survival; TMEV-OVA vaccination alone controlled tumor burden.
- In GL261-quad cassette glioma, vector silencing led to a decreased frequency of tumor antigen-specific CD8 T cells.
- The virus vector-specific CD8 T cell response does not appear to compete with tumor antigen-specific CD8 T cells.
Conclusions:
- Virus vector-specific CD8 T cell responses do not compete with tumor antigen-specific CD8 T cells in this model.
- Vector silencing, intended to enhance anti-tumor immunity, may paradoxically reduce the desired tumor antigen-specific CD8 T cell response, particularly in glioma.
- These findings have implications for optimizing virus vector-based immunotherapies and highlight potential risks of vector silencing strategies.
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