Abstract LB353: The switch from cap-dependent to cap-independent translation reshapes the immunopeptidome of lung cancer

Abstract

Abstract Cancer immunosurveillance relies on the presentation of peptide antigens on human leuckocyte antigen class I (HLA-I). HLA-I molecules present a diverse array of antigens, known as the “immunopeptidome”, which are recognized by cytotoxic CD8+ T cells. Recent evidence suggests that cryptic peptide antigens derived from non-canonical open reading frames (nuORFs) contribute to the immunopeptidome and drive CD8+ T cell responses. Integrating ribosome profiling (Ribo-seq) with mass spectrometry (MS) analyses has enabled the identification of several cryptic peptides derived from nuORFs including from putative non-coding regions including the 5’UTR, 3’UTR, long non coding RNAs (lncRNAs) and retained introns. Notably, many nuORFs undergo cap-independent translation. Various physiological and pharmacological stressors arrest canonical cap-dependent translation initiation and induce cap-independent translation. However, how this shift in translational dynamics influences the immunopeptidome is unknown. Using lung cancer cell lines, we show that the eIF4A inhibitor silvestrol induces cap-independent translation and reshapes the landscape of nuORF-derived peptide antigens. Silvestrol induced changes in the immunopeptidome strongly contrast with the global translation inhibitor homoharringtonine, which dampens antigen presentation. These observations suggest that the presentation of nuORF antigens in lung cancer is dynamic and tightly controlled by translational dynamics. More broadly, our study provokes reconsideration of translation inhibitors as immunomodulatory drugs that can change the HLA-I antigen repertoire and generate peptides that can act as new targets for cancer immunotherapy. Citation Format: Anika N. Ali, Andrew D. Weeden, Alex M. Jaeger. The switch from cap-dependent to cap-independent translation reshapes the immunopeptidome of lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB353.