Pharmacologic modulation of RNA splicing enhances anti-tumor immunity

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-de...

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Vydáno v:	Cell Ročník 184; číslo 15; s. 4032
Hlavní autoři:	Lu, Sydney X, De Neef, Emma, Thomas, James D, Sabio, Erich, Rousseau, Benoit, Gigoux, Mathieu, Knorr, David A, Greenbaum, Benjamin, Elhanati, Yuval, Hogg, Simon J, Chow, Andrew, Ghosh, Arnab, Xie, Abigail, Zamarin, Dmitriy, Cui, Daniel, Erickson, Caroline, Singer, Michael, Cho, Hana, Wang, Eric, Lu, Bin, Durham, Benjamin H, Shah, Harshal, Chowell, Diego, Gabel, Austin M, Shen, Yudao, Liu, Jing, Jin, Jian, Rhodes, Matthew C, Taylor, Richard E, Molina, Henrik, Wolchok, Jedd D, Merghoub, Taha, Diaz, Jr, Luis A, Abdel-Wahab, Omar, Bradley, Robert K
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 22.07.2021
Témata:	Animals Antigen Presentation - drug effects Antigen Presentation - immunology Antigens, Neoplasm - metabolism Cell Line, Tumor Cell Proliferation - drug effects Epitopes - immunology Ethylenediamines - pharmacology Gene Expression Regulation, Neoplastic - drug effects Hematopoiesis - drug effects Hematopoiesis - genetics Histocompatibility Antigens Class I - metabolism Humans Immune Checkpoint Inhibitors - pharmacology Immunotherapy Inflammation - pathology Mice Mice, Inbred C57BL Neoplasms - genetics Neoplasms - immunology Peptides - metabolism Protein Isoforms - metabolism Pyrroles - pharmacology RNA Splicing - drug effects RNA Splicing - genetics Sulfonamides - pharmacology T-Lymphocytes - drug effects T-Lymphocytes - immunology RBM39 neoepitopes PRMTs immunotherapy immunopeptidome neoantigens splicing PD1 RNA splicing immune checkpoint blockade
ISSN:	1097-4172, 1097-4172
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Popis
Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1097-4172 1097-4172
DOI:	10.1016/j.cell.2021.05.038