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Identification of the receptor of oncolytic virus M1 as a therapeutic predictor for multiple solid tumors
Deli Song1, Xudong Jia2, Xincheng Liu1
1Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.
Abstract:
Over the last decade, oncolytic virus (OV) therapy has shown its promising potential in tumor treatment. The fact that not every patient can benefit from it highlights the importance for defining biomarkers that help predict patients' responses. As particular self-amplifying biotherapeutics, the anti-tumor effects of OVs are highly dependent on the host factors for viral infection and replication. By using weighted gene co-expression network analysis (WGCNA), we found matrix remodeling associated 8 (MXRA8) is positively correlated with the oncolysis induced by oncolytic virus M1 (OVM). Consistently, MXRA8 promotes the oncolytic efficacy of OVM in vitro and in vivo. Moreover, the interaction of MXRA8 and OVM studied by single-particle cryo-electron microscopy (cryo-EM) showed that MXRA8 directly binds to this virus. Therefore, MXRA8 acts as the entry receptor of OVM. Pan-cancer analysis showed that MXRA8 is abundant in most solid tumors and is highly expressed in tumor tissues compared with adjacent normal ones. Further study in cancer cell lines and patient-derived tumor tissues revealed that the tumor selectivity of OVM is predominantly determined by a combinational effect of the cell membrane receptor MXRA8 and the intracellular factor, zinc-finger antiviral protein (ZAP). Taken together, our study may provide a novel dual-biomarker for precision medicine in OVM therapy.
Insights
Matrix remodeling associated 8 (MXRA8) acts as the entry receptor for oncolytic virus M1 (OVM), improving its tumor-killing ability. This discovery identifies MXRA8 and ZAP as dual biomarkers for precision OVM therapy.
Area of Science:
- Oncology
- Virology
- Molecular Biology
Background:
- Oncolytic virus (OV) therapy shows promise for cancer treatment but lacks predictive biomarkers for patient response.
- OV efficacy depends on host factors influencing viral infection and replication.
Purpose of the Study:
- To identify host factors and biomarkers predicting response to oncolytic virus M1 (OVM).
- To elucidate the mechanism of OVM entry and tumor selectivity.
Main Methods:
- Weighted gene co-expression network analysis (WGCNA) to identify host factors correlated with oncolysis.
- In vitro and in vivo experiments to assess the role of MXRA8 in OVM efficacy.
- Single-particle cryo-electron microscopy (cryo-EM) to determine the interaction between MXRA8 and OVM.
- Pan-cancer analysis and studies in cancer cell lines and patient-derived tissues to evaluate biomarker potential.
Main Results:
- Matrix remodeling associated 8 (MXRA8) was identified as a factor positively correlated with OVM-induced oncolysis.
- MXRA8 directly binds to OVM, functioning as its entry receptor and promoting viral efficacy.
- MXRA8 is highly expressed in most solid tumors compared to adjacent normal tissues.
- OVM tumor selectivity is determined by both MXRA8 and the intracellular factor, zinc-finger antiviral protein (ZAP).
Conclusions:
- MXRA8 is the direct entry receptor for oncolytic virus M1 (OVM).
- The combination of MXRA8 and ZAP serves as a dual biomarker for predicting OVM therapy response.
- This study provides a basis for precision medicine strategies in OVM therapy.
