Inducible de novo expression of neoantigens in tumor cells and mice.
Journal
Nature biotechnology
ISSN: 1546-1696
Titre abrégé: Nat Biotechnol
Pays: United States
ID NLM: 9604648
Informations de publication
Date de publication:
01 2021
01 2021
Historique:
received:
02
12
2019
accepted:
23
06
2020
revised:
13
06
2020
pubmed:
29
7
2020
medline:
12
2
2021
entrez:
29
7
2020
Statut:
ppublish
Résumé
Inducible expression of neoantigens in mice would enable the study of endogenous antigen-specific naïve T cell responses in disease and infection, but has been difficult to generate because leaky antigen expression in the thymus results in central T cell tolerance. Here we develop inversion-induced joined neoantigen (NINJA), using RNA splicing, DNA recombination and three levels of regulation to prevent leakiness and allow tight control over neoantigen expression. We apply NINJA to create tumor cell lines with inducible neoantigen expression, which could be used to study antitumor immunity. We also show that the genetic regulation in NINJA mice bypasses central and peripheral tolerance mechanisms and allows for robust endogenous CD8 and CD4 T cell responses on neoantigen induction in peripheral tissues. NINJA will enable studies of how T cells respond to defined neoantigens in the context of peripheral tolerance, transplantation, autoimmune diseases and cancer.
Identifiants
pubmed: 32719479
doi: 10.1038/s41587-020-0613-1
pii: 10.1038/s41587-020-0613-1
pmc: PMC7854852
mid: NIHMS1606636
doi:
Substances chimiques
Antigens, Neoplasm
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
64-73Subventions
Organisme : NIAID NIH HHS
ID : T32 AI007019
Pays : United States
Organisme : NCI NIH HHS
ID : K22 CA200912
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001863
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA237037
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK045735
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL007974
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016359
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK034989
Pays : United States
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