Abstract C070: Targeting neoantigens conserved across organs and species overcomes tumor immune escape

Abstract Neoantigen-targeted immunotherapies hold promise for cancer treatment, but current personalized approaches are time-consuming and costly. Here, we identify neoantigens encoded by Ptprs and Igf2r that are shared across murine mismatch repair-deficient colorectal and breast tumors and unexpectedly conserved in human colorectal, endometrial, gastric, and prostate cancers. These neoantigens elicit spontaneous, organ-spanning CD8+ T cell-mediated memory responses that are enhanced by immune checkpoint blockade. Vaccination with mRNA/lipid nanoparticles encoding these conserved neoantigens suppresses tumor growth across prophylactic and therapeutic models, including checkpoint-resistant orthotopic tumors. Tumor rejection is accompanied by antigen spreading, abscopal effects, and infiltration by clonally diverse T cells, dendritic cells, and MHC I/II+ macrophages producing CXCL9/10, CCL5/8, and TNF. Tumor cells also show activation of innate and adaptive pathways, including MHC and ISGs overexpression. Our results uncover a conserved anti-tumor immune mechanism and support the development of off-the-shelf neoantigen vaccines across tissues and species. Citation Format: Guillaume Mestrallet, Ross Ward, Matthew Brown, Jesse Boumelha, Frederika Rentzeperis, Natalie Vaninov, Miriam Saffern, Ezekiel Olumuyide, Prerna Suri, Sreekumar Balan, Leandra Velazquez, Aparna Ananthanarayanan, Zhihong Chen, Aimee Lucas, Miriam Merad, Cansu Cime-Bozkus, Nicolas Vabret, Robert Samstein, Nina Bhardwaj. Targeting neoantigens conserved across organs and species overcomes tumor immune escape [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr C070.