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bioRxiv · 10.64898/2026.02.10.705024

Harnessing Tumor-Specific Transcript Diversity Uncovers a Shared Neoantigen Reservoir for Pancreatic Ductal Adenocarcinoma

Zhao, J.·Li, Q.·Lin, P.·Yang, Y.·Yu, H.·Wen, Y.·Yu, W.·He, H.·Tao, S.·Zhang, F.·Li, Y.·Hu, Z.·Xie, J.·Chen, Z.·Huang, S.
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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is refractory to immunotherapy due to its immunologically cold microenvironment and the scarcity of mutation-derived neoantigens. Here, we introduce NeoAPP, a computational tool designed to systematically decode neoantigens arising from tumor-specific transcripts (TSTs) generated by transcriptional dysregulation. Multi-cohort transcriptomic profiling of 413 PDAC samples using NeoAPP reveal a median of 351 neoantigens per sample derived from 56 neoantigen-encoding TSTs (neoTSTs), surpassing mutation-derived counterparts in both abundance and patient coverage. Mechanistic analyses show that non-canonical splicing junction and transposable element activation drive neoantigen generation, while FOXA2-regulated promoter usage constitutes a potential major source of neoTSTs. Tumor-derived neoTSTs are also detected in extracellular vesicles and cancer-associated fibroblasts, implicating stromal crosstalk in immune modulation. Vaccination with neoTSTs induce CD8+ T cell responses in HLA-A*02:01/A*11:01 transgenic mice and suppressed tumor growth in syngeneic PDAC models. Collectively, this work establishes TST-derived neoantigens as a dominant and therapeutically actionable antigen reservoir in PDAC, advancing a transcriptome-guided framework for neoantigen discovery with potential to overcome immune resistance in low-mutation cancers. Abstract Figure O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=196 SRC="FIGDIR/small/705024v1_ufig1.gif" ALT="Figure 1"> View larger version (71K): org.highwire.dtl.DTLVardef@82ff31org.highwire.dtl.DTLVardef@401342org.highwire.dtl.DTLVardef@b0771corg.highwire.dtl.DTLVardef@15c03ef_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Zhao, J., Li, Q., Lin, P., Yang, Y., Yu, H., Wen, Y., Yu, W., He, H., Tao, S., Zhang, F., Li, Y., Hu, Z., Xie, J., Chen, Z., Huang, S.. 2026-02-12. Harnessing Tumor-Specific Transcript Diversity Uncovers a Shared Neoantigen Reservoir for Pancreatic Ductal Adenocarcinoma. https://doi.org/10.64898/2026.02.10.705024

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