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Salvage therapy expands highly cytotoxic and metabolically fit resilient CD8(+) T cells via ME1 up-regulation

Patients with advanced cancers who either do not experience initial response to or progress while on immune checkpoint inhibitors (ICIs) receive salvage radiotherapy to reduce tumor burden and tumor-related symptoms. Occasionally, some patients experience substantial global tumor regression with a r...

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Autores principales: Gicobi, Joanina K., Mao, Zhiming, DeFranco, Grace, Hirdler, Jacob B., Li, Ying, Vianzon, Vianca V., Dellacecca, Emilia R., Hsu, Michelle A., Barham, Whitney, Yan, Yiyi, Mansfield, Aaron S., Lin, Yi, Wu, Xiaosheng, Hitosugi, Taro, Owen, Dawn, Grams, Michael P., Orme, Jacob J., Lucien, Fabrice, Zeng, Hu, Park, Sean S., Dong, Haidong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10651128/
https://www.ncbi.nlm.nih.gov/pubmed/37967193
http://dx.doi.org/10.1126/sciadv.adi2414
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author Gicobi, Joanina K.
Mao, Zhiming
DeFranco, Grace
Hirdler, Jacob B.
Li, Ying
Vianzon, Vianca V.
Dellacecca, Emilia R.
Hsu, Michelle A.
Barham, Whitney
Yan, Yiyi
Mansfield, Aaron S.
Lin, Yi
Wu, Xiaosheng
Hitosugi, Taro
Owen, Dawn
Grams, Michael P.
Orme, Jacob J.
Lucien, Fabrice
Zeng, Hu
Park, Sean S.
Dong, Haidong
author_facet Gicobi, Joanina K.
Mao, Zhiming
DeFranco, Grace
Hirdler, Jacob B.
Li, Ying
Vianzon, Vianca V.
Dellacecca, Emilia R.
Hsu, Michelle A.
Barham, Whitney
Yan, Yiyi
Mansfield, Aaron S.
Lin, Yi
Wu, Xiaosheng
Hitosugi, Taro
Owen, Dawn
Grams, Michael P.
Orme, Jacob J.
Lucien, Fabrice
Zeng, Hu
Park, Sean S.
Dong, Haidong
author_sort Gicobi, Joanina K.
collection PubMed
description Patients with advanced cancers who either do not experience initial response to or progress while on immune checkpoint inhibitors (ICIs) receive salvage radiotherapy to reduce tumor burden and tumor-related symptoms. Occasionally, some patients experience substantial global tumor regression with a rebound of cytotoxic CD8(+) T cells. We have termed the rebound of cytotoxic CD8(+) T cells in response to salvage therapy as T cell resilience and examined the underlying mechanisms of resilience. Resilient T cells are enriched for CX3CR1(+) CD8(+) T cells with low mitochondrial membrane potential, accumulate less reactive oxygen species (ROS), and express more malic enzyme 1 (ME1). ME1 overexpression enhanced the cytotoxicity and expansion of effector CD8(+) T cells partially via the type I interferon pathway. ME1 also increased mitochondrial respiration while maintaining the redox state balance. ME1 increased the cytotoxicity of peripheral lymphocytes from patients with advanced cancers. Thus, preserved resilient T cells in patients rebound after salvage therapy and ME1 enhances their resiliency.
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spelling pubmed-106511282023-11-15 Salvage therapy expands highly cytotoxic and metabolically fit resilient CD8(+) T cells via ME1 up-regulation Gicobi, Joanina K. Mao, Zhiming DeFranco, Grace Hirdler, Jacob B. Li, Ying Vianzon, Vianca V. Dellacecca, Emilia R. Hsu, Michelle A. Barham, Whitney Yan, Yiyi Mansfield, Aaron S. Lin, Yi Wu, Xiaosheng Hitosugi, Taro Owen, Dawn Grams, Michael P. Orme, Jacob J. Lucien, Fabrice Zeng, Hu Park, Sean S. Dong, Haidong Sci Adv Biomedicine and Life Sciences Patients with advanced cancers who either do not experience initial response to or progress while on immune checkpoint inhibitors (ICIs) receive salvage radiotherapy to reduce tumor burden and tumor-related symptoms. Occasionally, some patients experience substantial global tumor regression with a rebound of cytotoxic CD8(+) T cells. We have termed the rebound of cytotoxic CD8(+) T cells in response to salvage therapy as T cell resilience and examined the underlying mechanisms of resilience. Resilient T cells are enriched for CX3CR1(+) CD8(+) T cells with low mitochondrial membrane potential, accumulate less reactive oxygen species (ROS), and express more malic enzyme 1 (ME1). ME1 overexpression enhanced the cytotoxicity and expansion of effector CD8(+) T cells partially via the type I interferon pathway. ME1 also increased mitochondrial respiration while maintaining the redox state balance. ME1 increased the cytotoxicity of peripheral lymphocytes from patients with advanced cancers. Thus, preserved resilient T cells in patients rebound after salvage therapy and ME1 enhances their resiliency. American Association for the Advancement of Science 2023-11-15 /pmc/articles/PMC10651128/ /pubmed/37967193 http://dx.doi.org/10.1126/sciadv.adi2414 Text en Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
spellingShingle Biomedicine and Life Sciences
Gicobi, Joanina K.
Mao, Zhiming
DeFranco, Grace
Hirdler, Jacob B.
Li, Ying
Vianzon, Vianca V.
Dellacecca, Emilia R.
Hsu, Michelle A.
Barham, Whitney
Yan, Yiyi
Mansfield, Aaron S.
Lin, Yi
Wu, Xiaosheng
Hitosugi, Taro
Owen, Dawn
Grams, Michael P.
Orme, Jacob J.
Lucien, Fabrice
Zeng, Hu
Park, Sean S.
Dong, Haidong
Salvage therapy expands highly cytotoxic and metabolically fit resilient CD8(+) T cells via ME1 up-regulation
title Salvage therapy expands highly cytotoxic and metabolically fit resilient CD8(+) T cells via ME1 up-regulation
title_full Salvage therapy expands highly cytotoxic and metabolically fit resilient CD8(+) T cells via ME1 up-regulation
title_fullStr Salvage therapy expands highly cytotoxic and metabolically fit resilient CD8(+) T cells via ME1 up-regulation
title_full_unstemmed Salvage therapy expands highly cytotoxic and metabolically fit resilient CD8(+) T cells via ME1 up-regulation
title_short Salvage therapy expands highly cytotoxic and metabolically fit resilient CD8(+) T cells via ME1 up-regulation
title_sort salvage therapy expands highly cytotoxic and metabolically fit resilient cd8(+) t cells via me1 up-regulation
topic Biomedicine and Life Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10651128/
https://www.ncbi.nlm.nih.gov/pubmed/37967193
http://dx.doi.org/10.1126/sciadv.adi2414
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