Abstract Dysregulated mRNA translation is often observed in cancer and is an emerging mechanism of oncogene expression and modulation of immune response in cancer. Pancreatic adenocarcinoma (PDAC) is a highly aggressive and challenging form of cancer with a 5-year survival rate of 13% that urgently requires novel therapeutic approaches. PDAC is characterized by low mutation rates, an immunologically suppressive environment, and resistance to immunotherapy, highlighting the need for new insights into the mechanisms of immune recognition and the discovery of tumor-specific antigens. Our work addresses the unmet need to discover the neoantigens and improve the treatment modalities in PDAC. Our and other’s work have previously established that RNA helicase EIF4A (Eukaryotic Initiation Factor 4A) dependent mRNA translation contribute to oncogenic programs and modulate immune response, offering potential therapeutic targets to inhibit PDAC growth. In this study we have mapped the translational landscape and mRNA Translation Start Site (RTSS) in PDAC cells following EIF4A inhibitor CR-1-31B treatment. CR-1-31B suppress cap-dependent mRNA translation while preserving and upregulating the mRNA translation of HLA Class I proteins including HLA-A/B/C (Human Leukocyte Antigen) and B2M (b-2 microglobulin). Next, we establish that CR-1-31B promotes immune checkpoint blockade protein PD-L1 expression. Interestingly while EIF4A inhibition results in downregulation of cap-dependent mRNA translation we observed a significant increase in the translation products arising from the usage of alternate RTSS in PDAC cells. Further we show that these non-canonical translation products can generate immunogenic peptides that can be presented by HLA Class I and elicit T cell activation in vitro. These neoantigens are not dependent on the somatic mutational status of cancer and hence, are particularly interesting for solid tumors with low somatic mutational burden such as PDAC. Our key findings show that targeting EIF4A using CR-1-31B converts PDAC tumors from an immunologically “cold” tumor to an immunologically “hot” tumor in a multifaceted fashion, by 1) promoting non-canonical translation products driven neoantigens, 2) enhancing protein production of HLA Class I proteins, and 3) upregulating expression of PD-L1, and 4) further sensitizing CR-1-31B treated tumors to anti-PD-L1 immune checkpoint blockade therapy. Our study establishes the contributions of each of these aspects on promoting anti-tumor immunity with the objective of developing a new treatment modality for PDAC. Citation Format: Kamini Singh. EIF4A Blockade Drives Neoantigen Generation and Immune Remodeling in Pancreatic Cancer 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 B047.
Kamini Singh (Wed,) studied this question.