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.

Oncolytic viruses are potent anticancer agents that replicate within and kill cancer cells rather than normal cells, and their selectivity is largely determined by oncogenic mutations. M1, a novel oncolytic virus strain, has been shown to target cancer cells, but the relationship between its cancer selectivity and oncogenic signaling pathways is poorly understood. Here, we report that RAS mutation promotes the replication and oncolytic effect of M1 in cancer, and we further provide evidence that the inhibition of the RAS/RAF/MEK signaling axis suppresses M1 infection and the subsequent cytopathic effects. Transcriptome analysis revealed that the inhibition of RAS signaling upregulates the type I interferon antiviral response, and further RNA interference screen identified CDKN1A as a key downstream factor that inhibits viral infection. Gain-and loss-of-function experiments confirmed that CDKN1A inhibited the replication and oncolytic effect of M1 virus. Subsequent TCGA data mining and tissue microarray (TMA) analysis revealed that CDKN1A is commonly deficient in human cancers, suggesting extensive clinical application prospects for M1. Our report indicates that virotherapy is feasible for treating undruggable RASdriven cancers and provides reliable biomarkers for personalized cancer therapy.

Background:We have previously identified a naturally occurring alphavirus (M1) as an innovative oncolytic virus that targets tumors deficient in zinc-finger antiviral protein (ZAP). Although amount of studies reported that oncolytic viruses promote the anti-tumor activity of macrophages, the antiviral effect of macrophages and how it is affected by tumor is still largely unknown.Methods: Using polycarbonate membrane inserts to establish co-culture model in which Murine macrophages Raw264.7 were co-cultured with itself or tumor cells (4T1 or B16F10). Flow cytometry, qRT-PCR, TCID50 assay, and Transcriptome sequencing were performed to determine the phenomenon and underlying mechanism of enhanced M1 virus replication in Tumor-conditioned macrophages. Results:We first discovered that Oncolytic virus M1 can infect in and be eliminated by the macrophage. Furthermore, Tumor co-cultured treatment sensitized Raw264.7 macrophages to M1 replication and impeded M1 clearance from Raw 264.7. Finally, knock-down of HPGD in Raw264.7 showed similar M1-sensitive phenotype. Conclusion:Tumor-derived factors inhibited antiviral immunity of Raw264.7 macrophages to M1 virus, which is associated with down-regulation of HPGD. This phenomenon may provide new insight into tumor selectivity of the M1 virus.