Pharmacologic modulation of RNA splicing enhances anti-tumor immunity
| Autor: | Eric Wang, Mathieu Gigoux, Sydney X. Lu, Benjamin H. Durham, Luis A. Diaz, Harshal Shah, Erich Sabio, Abigail Xie, Henrik Molina, Arnab Ghosh, Matthew C. Rhodes, Caroline Erickson, Jian Jin, Austin M. Gabel, Jedd D. Wolchok, Dmitriy Zamarin, Daniel Cui, Diego Chowell, Michael E Singer, Benjamin D. Greenbaum, Simon J. Hogg, Richard E. Taylor, James D. Thomas, Omar Abdel-Wahab, Taha Merghoub, Yudao Shen, Andrew Chow, Jing Liu, Hana Cho, David A. Knorr, Yuval Elhanati, Bin Lu, Emma De Neef, Benoit Rousseau, Robert K. Bradley |
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| Rok vydání: | 2020 |
| Předmět: |
medicine.medical_treatment
RNA Splicing T-Lymphocytes Biology Major histocompatibility complex General Biochemistry Genetics and Molecular Biology Epitope 03 medical and health sciences Epitopes 0302 clinical medicine Antigens Neoplasm Cell Line Tumor Neoplasms MHC class I medicine Animals Humans Protein Isoforms Pyrroles Immune Checkpoint Inhibitors 030304 developmental biology Cell Proliferation Inflammation 0303 health sciences Antigen Presentation Sulfonamides Histocompatibility Antigens Class I Immunotherapy Ethylenediamines Immune checkpoint Cell biology Blockade Hematopoiesis Gene Expression Regulation Neoplastic Mice Inbred C57BL Cancer cell RNA splicing biology.protein Peptides 030217 neurology & neurosurgery |
| Zdroj: | Cell. 184(15) |
| ISSN: | 1097-4172 |
| Popis: | Summary 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. |
| Databáze: | OpenAIRE |
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