Inducible de novo expression of neoantigens in tumor cells and mice

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...

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Published in:Nature biotechnology 2021-01, Vol.39 (1), p.64-73
Main Authors: 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, Chang, Greg P., Gocheva, Vasilena, Schmidt, Leah M., Boileve, Alice, Wilson, Josephine H., Cui, Can, Monroy, Isabel, Gokare, Prashanth, Cabeceiras, Peter, Jacks, Tyler, Joshi, Nikhil S.
Format: Article
Language:English
Subjects:
631/1647/767/1972
631/250/2152/569/2494
631/250/2152/569/2495
631/61/17/1511
Agriculture
Analysis
Animals
Antigens
Antigens, Neoplasm - genetics
Antigens, Neoplasm - metabolism
Autoimmune diseases
Bioinformatics
Biomedical and Life Sciences
Biomedical Engineering/Biotechnology
Biomedicine
Biotechnology
Cancer
CD4 antigen
CD4-Positive T-Lymphocytes - chemistry
CD4-Positive T-Lymphocytes - metabolism
CD8 antigen
CD8-Positive T-Lymphocytes - chemistry
CD8-Positive T-Lymphocytes - metabolism
Cell Engineering - methods
Deoxyribonucleic acid
DNA
Female
Gene expression
Genetic aspects
Health aspects
Humans
Immunological tolerance
Life Sciences
Lymphocytes
Lymphocytes T
Mice
Neoantigens
Oncology, Experimental
Organ Specificity - genetics
Recombination
Ribonucleic acid
RNA
RNA Splicing - genetics
Splicing
T cells
Transplantation
Tumor antigens
Tumor cell lines
Tumor cells
Tumor Cells, Cultured
Tumors
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cited_by cdi_FETCH-LOGICAL-c618t-d36c4ae539b4825c3a839a846d0e9c4522c0d7d34abdc551cfa1cacbac5d1133
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container_end_page 73
container_issue 1
container_start_page 64
container_title Nature biotechnology
container_volume 39
creator 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
Chang, Greg P.
Gocheva, Vasilena
Schmidt, Leah M.
Boileve, Alice
Wilson, Josephine H.
Cui, Can
Monroy, Isabel
Gokare, Prashanth
Cabeceiras, Peter
Jacks, Tyler
Joshi, Nikhil S.
description 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. A system to express neoantigens in tumor cells and mice circumvents central T cell tolerance.
doi_str_mv 10.1038/s41587-020-0613-1
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Biotechnol</addtitle><date>2021-01-01</date><risdate>2021</risdate><volume>39</volume><issue>1</issue><spage>64</spage><epage>73</epage><pages>64-73</pages><issn>1087-0156</issn><issn>1546-1696</issn><eissn>1546-1696</eissn><abstract>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. A system to express neoantigens in tumor cells and mice circumvents central T cell tolerance.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>32719479</pmid><doi>10.1038/s41587-020-0613-1</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0002-7960-5445</orcidid><orcidid>https://orcid.org/0000-0001-5785-8911</orcidid><orcidid>https://orcid.org/0000-0003-3482-0579</orcidid><orcidid>https://orcid.org/0000-0002-7217-3221</orcidid><orcidid>https://orcid.org/0000-0003-4736-4330</orcidid><orcidid>https://orcid.org/0000-0003-1346-0930</orcidid><orcidid>https://orcid.org/0000-0002-7045-7837</orcidid><oa>free_for_read</oa></addata></record>
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identifier ISSN: 1087-0156
ispartof Nature biotechnology, 2021-01, Vol.39 (1), p.64-73
issn 1087-0156
1546-1696
1546-1696
language eng
recordid cdi_proquest_miscellaneous_2428065335
source Nature Journals
subjects 631/1647/767/1972
631/250/2152/569/2494
631/250/2152/569/2495
631/61/17/1511
Agriculture
Analysis
Animals
Antigens
Antigens, Neoplasm - genetics
Antigens, Neoplasm - metabolism
Autoimmune diseases
Bioinformatics
Biomedical and Life Sciences
Biomedical Engineering/Biotechnology
Biomedicine
Biotechnology
Cancer
CD4 antigen
CD4-Positive T-Lymphocytes - chemistry
CD4-Positive T-Lymphocytes - metabolism
CD8 antigen
CD8-Positive T-Lymphocytes - chemistry
CD8-Positive T-Lymphocytes - metabolism
Cell Engineering - methods
Deoxyribonucleic acid
DNA
Female
Gene expression
Genetic aspects
Health aspects
Humans
Immunological tolerance
Life Sciences
Lymphocytes
Lymphocytes T
Mice
Neoantigens
Oncology, Experimental
Organ Specificity - genetics
Recombination
Ribonucleic acid
RNA
RNA Splicing - genetics
Splicing
T cells
Transplantation
Tumor antigens
Tumor cell lines
Tumor cells
Tumor Cells, Cultured
Tumors
title Inducible de novo expression of neoantigens in tumor cells and mice
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