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Differential roles of type I interferon signaling in tumor versus host cells in experimental glioma models
Evelina Blomberg1, Manuela Silginer2, Patrick Roth3
1Laboratory of Molecular Neuro-Oncology, Department of Neurology, University of Zürich.
Abstract:
Despite multimodal treatment approaches including surgery, radiotherapy and chemotherapy, the median survival for patients with glioblastoma remains in the range of one year and thus poor. Type I interferons (IFN) are involved in immune responses to viral infection and exhibit anti-tumor activity in certain cancers. Here we explored the biological relevance of constitutive type I IFN signaling in murine glioma models in vitro and in vivo. CT-2A, GL-261, SMA-497, SMA-540 and SMA-560 murine glioma cells expressed IFN type I receptors IFNAR1 and IFNAR2 and were responsive to exogenous IFN stimulation. CRISPR/Cas9-mediated deletion of IFNAR1 decreased the baseline expression of type I IFN response genes in GL-261 cells, but neither in CT-2A nor in SMA-560 cells. IFNAR1 deletion slowed growth in GL-261 and SMA-560, but not in CT-2A cells. However, only the growth of IFNAR1-depleted GL-261 tumors and not that of SMA-560 tumors was delayed in vivo upon orthotopic tumor cell implantation into syngeneic mice. This survival gain was no longer detected when the IFNAR1-depleted GL-261 cells were inoculated into IFNAR1-deficient mice. Altogether these data suggest that constitutive type I IFN signaling in gliomas may be pro-tumorigenic, but only in a microenvironment that is proficient for type I IFN signaling in the host.
Insights
Constitutive type I interferon (IFN) signaling in glioma cells can promote tumor growth. This effect depends on the host
Area of Science:
- Neuro-oncology
- Immunology
- Cancer Biology
Background:
- Glioblastoma (GBM) has a poor prognosis despite aggressive multimodal treatments.
- Type I interferons (IFNs) are crucial in antiviral immunity and have shown anti-tumor potential in some cancers.
- The role of constitutive type I IFN signaling in glioma remains unclear.
Purpose of the Study:
- To investigate the biological significance of constitutive type I IFN signaling in preclinical murine glioma models.
- To determine whether type I IFN signaling in glioma cells is pro- or anti-tumorigenic.
- To elucidate the influence of the host microenvironment on type I IFN signaling in glioma.
Main Methods:
- Utilized various murine glioma cell lines (CT-2A, GL-261, SMA-497, SMA-540, SMA-560) expressing type I IFN receptors (IFNAR1, IFNAR2).
- Employed CRISPR/Cas9 gene editing to delete IFNAR1 in glioma cells.
- Assessed in vitro cell growth and in vivo tumor development following orthotopic implantation in syngeneic and IFNAR1-deficient mice.
Main Results:
- Glioma cells expressed functional type I IFN receptors and responded to exogenous IFN.
- IFNAR1 deletion reduced baseline type I IFN response gene expression in GL-261 cells.
- IFNAR1 deletion impaired tumor growth in GL-261 and SMA-560 cells in vitro, but only GL-261 tumor growth was significantly delayed in vivo.
- The pro-tumorigenic effect of IFNAR1 deletion in GL-261 cells was abrogated in IFNAR1-deficient host mice.
Conclusions:
- Constitutive type I IFN signaling in glioma cells can be pro-tumorigenic.
- The pro-tumorigenic effect is dependent on the presence of type I IFN signaling in the host microenvironment.
- These findings highlight the complex interplay between tumor-intrinsic and host-derived type I IFN signaling in glioma progression.
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