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Inducible de novo expression of neoantigens in tumor cells and mice
Name
nihms-1606636.pdf
Description
Accepted version
Size
3.69 MB
Format
Adobe PDF
Checksum (MD5)
71fa4ef59d8bcaba797266f49b09d1d9
Author(s)
Damo, Martina
Fitzgerald, Brittany
Lu, Yisi
Nader, Mursal
William, Ivana
Cheung, Julie F
Connolly, Kelli A
Foster, Gena G
Akama-Garren, Elliot
Lee, Da-Yae
Date Issued
2021
Journal
Nature Biotechnology
Publisher
Springer Science and Business Media LLC
Version
Author's final manuscript
Abstract
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. 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.
Terms of Use
Creative Commons Attribution-Noncommercial-Share Alike
Persistent DSpace Link
DOI of Published Version
10.1038/S41587-020-0613-1
