Oncolytic virotherapy induced CSDE1 neo-antigenesis restricts VSV replication but can be targeted by immunotherapy

Area of Science:

• Oncology
• Virology
• Immunology

Background:

• Oncolytic vesicular stomatitis virus expressing interferon beta (VSV-IFNβ) shows initial efficacy but is followed by aggressive tumor relapse in clinical trials.
• Tumor escape mechanisms limit the effectiveness of oncolytic viral therapies.

Purpose of the Study:

• To investigate the molecular mechanisms of VSV-IFNβ therapy escape.
• To identify strategies for preventing tumor relapse and enhancing oncolytic virotherapy efficacy.

Main Methods:

• Analysis of tumor samples from patients experiencing relapse after VSV-IFNβ treatment.
• Genetic sequencing to identify mutations in escape tumors.
• In vitro studies to assess the impact of CSDE1 mutations on viral replication.
• Development and testing of a vaccination strategy targeting the mutated protein.

Main Results:

• VSV-IFNβ-escape tumors consistently express a mutated form of the RNA-binding protein, CSDE1^P5S.
• CSDE1^P5S inhibits VSV replication by disrupting viral transcription, promoting tumor escape.
• The virus evolves compensatory mutations to overcome CSDE1^P5S-mediated inhibition.
• CSDE1^P5S presents a neo-epitope recognized by T cells, enabling a targeted immune response.
• Vaccination against CSDE1^P5S prevents tumor escape and relapse.

Conclusions:

• CSDE1 is a critical cellular co-factor for VSV replication, and its mutation drives therapeutic escape.
• CSDE1^P5S acts as a neo-antigen, offering a target for immunotherapy.
• Combining oncolytic virotherapy with CSDE1^P5S-targeted vaccination can prevent tumor escape and acquired resistance, applicable to various cancer therapies.