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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...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2020
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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. |
format | Online Article Text |
id | pubmed-7105382 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
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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