Site-specific neoepitope induction by RNA editing reprograms tumor immunogenicity

Area of Science:

• Immunology
• Cancer Research
• Molecular Biology

Background:

• Neoantigens are highly immunogenic but their stochastic nature and limited availability in low mutational burden cancers restrict personalized cancer vaccine design.
• Current neoantigen-based immunotherapies face challenges due to the need for personalized vaccine development and insufficient neoantigen targets in certain cancers.

Purpose of the Study:

• To introduce a novel strategy, RNA Editing-Induced Site-specific Neoantigen (REISN), to engineer tumor immunogenicity by targeting shared antigens.
• To evaluate the immunogenicity and antitumor efficacy of REISN-based vaccination.

Main Methods:

• Utilized an MS2 coat protein (MCP)-ADAR-based A-to-I RNA editing system to modify T cell receptor (TCR)-contact residues in MHC-I presented peptides from cancer-testis antigen P1A and embryonic antigen AFP.
• Developed lipid nanoparticle-formulated P1A-REISN circular RNA for vaccination.
• Assessed REISN-specific T cell activation and antitumor effects in immunocompetent mice.

Main Results:

• Site-directed RNA editing successfully generated REISN-modified epitopes that activated REISN-specific naive T cells.
• Vaccination with P1A-REISN circular RNA induced potent antigen-specific CD8+ T cell responses.
• REISN vaccination suppressed tumor growth in mice.

Conclusions:

• Site-directed RNA editing can reprogram tumor immunogenicity by creating defined neoantigen-like epitopes from shared tumor-associated antigens.
• The REISN strategy shows promise for expanding neoantigen-based immunotherapy to cancers with low mutational burden.
• This approach warrants further investigation for clinical translation.