| Literature DB >> 34171309 |
Sydney X Lu1, Emma De Neef2, James D Thomas3, Erich Sabio4, Benoit Rousseau5, Mathieu Gigoux6, David A Knorr5, Benjamin Greenbaum7, Yuval Elhanati7, Simon J Hogg8, Andrew Chow9, Arnab Ghosh9, Abigail Xie10, Dmitriy Zamarin9, Daniel Cui8, Caroline Erickson8, Michael Singer8, Hana Cho8, Eric Wang8, Bin Lu8, Benjamin H Durham8, Harshal Shah8, Diego Chowell11, Austin M Gabel12, Yudao Shen13, Jing Liu13, Jian Jin13, Matthew C Rhodes14, Richard E Taylor14, Henrik Molina15, Jedd D Wolchok9, Taha Merghoub9, Luis A Diaz5, Omar Abdel-Wahab16, Robert K Bradley17.
Abstract
Although mutations in DNA are the best-studied source of neoantigens that determine response to immune checkpoint blockade, alterations in RNA splicing within cancer cells could similarly result in neoepitope production. However, the endogenous antigenicity and clinical potential of such splicing-derived epitopes have not been tested. Here, we demonstrate that pharmacologic modulation of splicing via specific drug classes generates bona fide neoantigens and elicits anti-tumor immunity, augmenting checkpoint immunotherapy. Splicing modulation inhibited tumor growth and enhanced checkpoint blockade in a manner dependent on host T cells and peptides presented on tumor MHC class I. Splicing modulation induced stereotyped splicing changes across tumor types, altering the MHC I-bound immunopeptidome to yield splicing-derived neoepitopes that trigger an anti-tumor T cell response in vivo. These data definitively identify splicing modulation as an untapped source of immunogenic peptides and provide a means to enhance response to checkpoint blockade that is readily translatable to the clinic.Entities:
Keywords: PD1; PRMTs; RBM39; RNA splicing; immune checkpoint blockade; immunopeptidome; immunotherapy; neoantigens; neoepitopes; splicing
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Year: 2021 PMID： 34171309 PMCID： PMC8684350 DOI： 10.1016/j.cell.2021.05.038
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 66.850