NMD inhibition by 5-azacytidine augments presentation of immunogenic frameshift-derived neoepitopes

被引:25
作者
Becker, Jonas P. [1 ,2 ,3 ,4 ]
Helm, Dominic [5 ]
Rettel, Mandy [2 ]
Stein, Frank [2 ]
Hernandez-Sanchez, Alejandro [1 ,2 ,6 ,7 ]
Urban, Katharina [1 ,2 ,6 ,7 ]
Gebert, Johannes [1 ,2 ,6 ,7 ]
Kloor, Matthias [1 ,2 ,6 ,7 ]
Neu-Yilik, Gabriele [1 ,2 ,3 ,4 ]
Doeberitz, Magnus von Knebel [1 ,2 ,6 ,7 ]
Hentze, Matthias W. [1 ,2 ]
Kulozik, Andreas E. [1 ,2 ,3 ,4 ]
机构
[1] Heidelberg Univ, Mol Med Partnership Unit MMPU, D-69120 Heidelberg, Germany
[2] European Mol Biol Lab EMBL, D-69117 Heidelberg, Germany
[3] Heidelberg Univ, Dept Pediat Oncol Hematol & Immunol, D-69120 Heidelberg, Germany
[4] Natl Ctr Tumor Dis NCT, Hopp Childrens Canc Ctr, D-69120 Heidelberg, Germany
[5] German Canc Res Ctr, Genom & Prote Core Facil, D-69120 Heidelberg, Germany
[6] Heidelberg Univ, Inst Pathol, Dept Appl Tumor Biol, D-69120 Heidelberg, Germany
[7] German Canc Res Ctr, Collaborat Unit Appl Tumor Biol, D-69120 Heidelberg, Germany
关键词
NONSENSE-MEDIATED DECAY; MESSENGER-RNA DECAY; MASS-SPECTROMETRY; MICROSATELLITE INSTABILITY; R/BIOCONDUCTOR PACKAGE; HLA; NEOANTIGENS; IMMUNOPEPTIDOMICS; IDENTIFICATION; ABUNDANCE;
D O I
10.1016/j.isci.2021.102389
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
T Frameshifted protein sequences elicit tumor-specific T cell-mediated immune responses inmicrosatellite-unstable (MSI) cancers if presented by HLA class I molecules. However, their expression and presentation are limited by nonsense-mediated RNA decay (NMD). We employed an unbiased immunopeptidomics workflow to analyze MSI HCT-116 cells and identified >10,000 HLA class I-presented peptides including five frameshift-derived InDel neoepitopes. Notably, pharmacological NMD inhibition with 5-azacytidine stabilizes frameshift-bearing transcripts and increases the HLA class I-mediated presentation of InDel neoepitopes. The frameshift mutation underlying one of the identified InDel neoepitopes is highly recurrent in MSI colorectal cancer cell lines and primary patient samples, and immunization with the corresponding neoepitope induces strong CD8(+) T cell responses in an HLA-A*02: 01 transgenic mouse model. Our data show directly that pharmacological NMD inhibition augments HLA class I-mediated presentation of immunogenic frameshift-derived InDel neoepitopes thus highlighting the clinical potential of NMD inhibition in anti-cancer immunotherapy strategies.
引用
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页数:51
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