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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Veröffentlicht in:Cell Jg. 184; H. 15; S. 4032
Hauptverfasser: 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
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 22.07.2021
Schlagworte:
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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Zusammenfassung: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.
Bibliographie: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