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Tumors attenuating the mitochondrial activity in T cells escape from PD-1 blockade therapy

PD-1 blockade therapy has revolutionized cancer treatments. However, a substantial population of patients is unresponsive. To rescue unresponsive patients, the mechanism of unresponsiveness to PD-1 blockade therapy must be elucidated. Using a ‘bilateral tumor model’ where responsive and unresponsive...

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Detalles Bibliográficos
Autores principales: Kumar, Alok, Chamoto, Kenji, Chowdhury, Partha S, Honjo, Tasuku
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105382/
https://www.ncbi.nlm.nih.gov/pubmed/32122466
http://dx.doi.org/10.7554/eLife.52330
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author Kumar, Alok
Chamoto, Kenji
Chowdhury, Partha S
Honjo, Tasuku
author_facet Kumar, Alok
Chamoto, Kenji
Chowdhury, Partha S
Honjo, Tasuku
author_sort Kumar, Alok
collection PubMed
description PD-1 blockade therapy has revolutionized cancer treatments. However, a substantial population of patients is unresponsive. To rescue unresponsive patients, the mechanism of unresponsiveness to PD-1 blockade therapy must be elucidated. Using a ‘bilateral tumor model’ where responsive and unresponsive tumors were inoculated into different sides of the mouse belly, we demonstrated that unresponsive tumors can be categorized into two groups: with and without systemic immunosuppressive property (SIP). The SIP-positive tumors released uncharacterized, non-proteinaceous small molecules that inhibited mitochondrial activation and T cell proliferation. By contrast, the SIP-negative B16 tumor escaped from immunity by losing MHC class I expression. Unresponsiveness of SIP-positive tumors was partially overcome by improving the mitochondrial function with a mitochondrial activator; this was not successful for B16, which employs immune ignorance. These results demonstrated that the ‘bilateral tumor model’ was useful for stratifying tumors to investigate the mechanism of unresponsiveness and develop a strategy for proper combination therapy.
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spelling pubmed-71053822020-04-01 Tumors attenuating the mitochondrial activity in T cells escape from PD-1 blockade therapy Kumar, Alok Chamoto, Kenji Chowdhury, Partha S Honjo, Tasuku eLife Immunology and Inflammation PD-1 blockade therapy has revolutionized cancer treatments. However, a substantial population of patients is unresponsive. To rescue unresponsive patients, the mechanism of unresponsiveness to PD-1 blockade therapy must be elucidated. Using a ‘bilateral tumor model’ where responsive and unresponsive tumors were inoculated into different sides of the mouse belly, we demonstrated that unresponsive tumors can be categorized into two groups: with and without systemic immunosuppressive property (SIP). The SIP-positive tumors released uncharacterized, non-proteinaceous small molecules that inhibited mitochondrial activation and T cell proliferation. By contrast, the SIP-negative B16 tumor escaped from immunity by losing MHC class I expression. Unresponsiveness of SIP-positive tumors was partially overcome by improving the mitochondrial function with a mitochondrial activator; this was not successful for B16, which employs immune ignorance. These results demonstrated that the ‘bilateral tumor model’ was useful for stratifying tumors to investigate the mechanism of unresponsiveness and develop a strategy for proper combination therapy. eLife Sciences Publications, Ltd 2020-03-03 /pmc/articles/PMC7105382/ /pubmed/32122466 http://dx.doi.org/10.7554/eLife.52330 Text en © 2020, Kumar et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Immunology and Inflammation
Kumar, Alok
Chamoto, Kenji
Chowdhury, Partha S
Honjo, Tasuku
Tumors attenuating the mitochondrial activity in T cells escape from PD-1 blockade therapy
title Tumors attenuating the mitochondrial activity in T cells escape from PD-1 blockade therapy
title_full Tumors attenuating the mitochondrial activity in T cells escape from PD-1 blockade therapy
title_fullStr Tumors attenuating the mitochondrial activity in T cells escape from PD-1 blockade therapy
title_full_unstemmed Tumors attenuating the mitochondrial activity in T cells escape from PD-1 blockade therapy
title_short Tumors attenuating the mitochondrial activity in T cells escape from PD-1 blockade therapy
title_sort tumors attenuating the mitochondrial activity in t cells escape from pd-1 blockade therapy
topic Immunology and Inflammation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105382/
https://www.ncbi.nlm.nih.gov/pubmed/32122466
http://dx.doi.org/10.7554/eLife.52330
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