Ji et al. used full-length ribosome–nascent chain complex–bound mRNAseq (FL-RNCseq) and an AI-based prediction model (FIONA2) to profile neoepitope landscapes, including large-scale transcript variants (LSTVs) often missed by short-read sequencing. In MC38, the team identified LSTV-derived MHC-I and MHC-II neoepitopes and selected 22 to be encoded into an mRNA lipid nanoparticle vaccine, which induced T cell-mediated immunity (mainly CD4+), altered TMEs, reduced tumor growth, and protected mice prophylactically and from rechallenge. These effects were enhanced in combination with anti-PD-1, and showed favorable correlations in TCGA.
Contributed by Lauren Hitchings
ABSTRACT: Precise neoepitope discovery is crucial for effective cancer therapeutic vaccines. Conventional approaches struggle to build a repertoire with sufficient immunogenic epitopes. We developed a workflow leveraging full-length ribosome-nascent chain complex-bound mRNA sequencing (FL-RNC seq) and artificial intelligence-based predictive models to accurately identify the neoepitope landscape, especially large-scale transcript variants (LSTVs) missed by short-read sequencing. In the MC38 mouse model, we identified 22 LSTV-derived neoepitopes encoded by a synthesized mRNA lipid nanoparticle vaccine. As a standalone therapy and combined with anti-PD-1 immunotherapy, the vaccine curbed tumor progression, induced robust T cell-specific immunity, and modulated the tumor microenvironment. This underscores the multifaceted potentials of LSTV-derived vaccines. Our approach expands the neoepitope source repertoire, offering a method for discovering personalized cancer vaccines applicable to a broader tumor range. The results highlight the importance of comprehensive neoepitope identification and the promise of LSTV-based vaccines for cancer immunotherapy.
Author Info: (1) State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China. (2) State Key Laboratory of Pharmaceutical Biotechnolo
Author Info: (1) State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China. (2) State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China. (3) State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China. (4) State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China. (5) State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China. (6) State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China. (7) Nanjing Chengshi Biomedical Technology Co. Ltd., Nanjing 210031, China. (8) Nanjing Chengshi Biomedical Technology Co. Ltd., Nanjing 210031, China. (9) Nanjing Chengshi Biomedical Technology Co. Ltd., Nanjing 210031, China. (10) Nanjing Chengshi Biomedical Technology Co. Ltd., Nanjing 210031, China. (11) Nanjing Chengshi Biomedical Technology Co. Ltd., Nanjing 210031, China. (12) Nanjing Chengshi Biomedical Technology Co. Ltd., Nanjing 210031, China. (13) State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China. (14) State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China. (15) State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China. (16) State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China.
