Identification of TPRA1 as a Novel Receptor and Predictive Biomarker for Oncolytic Virus M1

Area of Science:

• Oncolytic virotherapy
• Molecular virology
• Cancer biology

Background:

• Oncolytic viruses selectively target cancer cells, with viral receptors determining tropism.
• Identifying these receptors is crucial for optimizing oncolytic virus therapy and patient selection.

Purpose of the Study:

• To identify novel host cell receptors for the oncolytic virus M1 (OVM).
• To elucidate the mechanism by which the identified receptor facilitates viral entry.
• To evaluate the identified receptor as a potential biomarker for OVM therapy response.

Main Methods:

• A membrane protein-targeted CRISPR-Cas9 screen was employed to identify OVM receptors.
• Mechanistic studies involving viral attachment, internalization, and binding assays were performed.
• TPRA1 expression levels were analyzed in cell lines, mouse models, and patient-derived tumor samples.

Main Results:

• Transmembrane protein adipocyte-associated 1 (TPRA1) was identified as a novel receptor for OVM.
• TPRA1 facilitates OVM infection by promoting viral attachment via glycosylation and internalization via its cytoplasmic tail.
• TPRA1 expression positively correlated with OVM sensitivity across various models and is upregulated in tumors compared to normal tissues.
• TPRA1 also mediates Semliki Forest Virus entry, indicating a conserved role in alphavirus infection.

Conclusions:

• TPRA1 is a key determinant of OVM tropism and viral entry.
• TPRA1 serves as a potential predictive biomarker for OVM therapy, aiding in patient selection for clinical trials.
• The findings advance the understanding of oncolytic virus-host interactions and therapeutic strategies.