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Chemical augmentation of mitochondrial electron transport chains tunes T cell activation threshold in tumors

BACKGROUND: Cancer immunotherapy shows insufficient efficacy for low immunogenic tumors. Furthermore, tumors often downregulate antigen and major histocompatibility complex expression to escape recognition by T cells, resulting in insufficient T cell receptor (TCR) stimulation in the tumor microenvi...

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Autores principales: Dotsu, Yosuke, Muraoka, Daisuke, Ogo, Naohisa, Sonoda, Yudai, Yasui, Kiyoshi, Yamaguchi, Hiroyuki, Yagita, Hideo, Mukae, Hiroshi, Asai, Akira, Ikeda, Hiroaki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8814813/
https://www.ncbi.nlm.nih.gov/pubmed/35115364
http://dx.doi.org/10.1136/jitc-2021-003958
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author Dotsu, Yosuke
Muraoka, Daisuke
Ogo, Naohisa
Sonoda, Yudai
Yasui, Kiyoshi
Yamaguchi, Hiroyuki
Yagita, Hideo
Mukae, Hiroshi
Asai, Akira
Ikeda, Hiroaki
author_facet Dotsu, Yosuke
Muraoka, Daisuke
Ogo, Naohisa
Sonoda, Yudai
Yasui, Kiyoshi
Yamaguchi, Hiroyuki
Yagita, Hideo
Mukae, Hiroshi
Asai, Akira
Ikeda, Hiroaki
author_sort Dotsu, Yosuke
collection PubMed
description BACKGROUND: Cancer immunotherapy shows insufficient efficacy for low immunogenic tumors. Furthermore, tumors often downregulate antigen and major histocompatibility complex expression to escape recognition by T cells, resulting in insufficient T cell receptor (TCR) stimulation in the tumor microenvironment. Thus, augmenting TCR-mediated recognition of tumor antigens is a useful strategy to improve the efficacy of cancer immunotherapy. METHODS: We screened 310 small molecules from our library and identified PQDN, a small molecule that activates CD8 T cells after TCR engagement, even when antigen stimulation is too weak for their activation. We used inhibitors of mitochondrial functions and Seahorse Flux Analyzer to investigate the mechanism underlying the effect of PQDN on T cells. Effect of PQDN on tumor-infiltrating CD8 T cells was examined using flow cytometry and TCR repertoire analysis. RESULTS: PQDN increased mitochondrial reciprocal capacity through enhancement of electron transport chains (ETCs) and facilitated glycolysis via mTOR/AKT signaling, resulting in augmented CD8 T cell activation, even when antigen stimulation is extremely weak. Intratumoral administration of this compound into tumor-bearing mice tunes inactivated T cell with tumor antigen recognition potent and expanded functional T cell receptor diversity of tumor-infiltrating T cells, augmenting antitumor immune responses and retarding tumor growth. Furthermore, PQDN has a synergistic potent with T cell dependent immunotherapy, such as checkpoint inhibitory therapy or adoptive cell therapy, even in a low immunogenic tumor. We also demonstrated that this compound enhances the activation of human CD8 T cells. CONCLUSIONS: These data suggest that tuning the T cell activation threshold by chemical activation of mitochondrial ETC is a new strategy for improving therapeutic efficacy through the activation of low-avidity tumor-specific T cells.
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spelling pubmed-88148132022-02-16 Chemical augmentation of mitochondrial electron transport chains tunes T cell activation threshold in tumors Dotsu, Yosuke Muraoka, Daisuke Ogo, Naohisa Sonoda, Yudai Yasui, Kiyoshi Yamaguchi, Hiroyuki Yagita, Hideo Mukae, Hiroshi Asai, Akira Ikeda, Hiroaki J Immunother Cancer Basic Tumor Immunology BACKGROUND: Cancer immunotherapy shows insufficient efficacy for low immunogenic tumors. Furthermore, tumors often downregulate antigen and major histocompatibility complex expression to escape recognition by T cells, resulting in insufficient T cell receptor (TCR) stimulation in the tumor microenvironment. Thus, augmenting TCR-mediated recognition of tumor antigens is a useful strategy to improve the efficacy of cancer immunotherapy. METHODS: We screened 310 small molecules from our library and identified PQDN, a small molecule that activates CD8 T cells after TCR engagement, even when antigen stimulation is too weak for their activation. We used inhibitors of mitochondrial functions and Seahorse Flux Analyzer to investigate the mechanism underlying the effect of PQDN on T cells. Effect of PQDN on tumor-infiltrating CD8 T cells was examined using flow cytometry and TCR repertoire analysis. RESULTS: PQDN increased mitochondrial reciprocal capacity through enhancement of electron transport chains (ETCs) and facilitated glycolysis via mTOR/AKT signaling, resulting in augmented CD8 T cell activation, even when antigen stimulation is extremely weak. Intratumoral administration of this compound into tumor-bearing mice tunes inactivated T cell with tumor antigen recognition potent and expanded functional T cell receptor diversity of tumor-infiltrating T cells, augmenting antitumor immune responses and retarding tumor growth. Furthermore, PQDN has a synergistic potent with T cell dependent immunotherapy, such as checkpoint inhibitory therapy or adoptive cell therapy, even in a low immunogenic tumor. We also demonstrated that this compound enhances the activation of human CD8 T cells. CONCLUSIONS: These data suggest that tuning the T cell activation threshold by chemical activation of mitochondrial ETC is a new strategy for improving therapeutic efficacy through the activation of low-avidity tumor-specific T cells. BMJ Publishing Group 2022-02-03 /pmc/articles/PMC8814813/ /pubmed/35115364 http://dx.doi.org/10.1136/jitc-2021-003958 Text en © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Basic Tumor Immunology
Dotsu, Yosuke
Muraoka, Daisuke
Ogo, Naohisa
Sonoda, Yudai
Yasui, Kiyoshi
Yamaguchi, Hiroyuki
Yagita, Hideo
Mukae, Hiroshi
Asai, Akira
Ikeda, Hiroaki
Chemical augmentation of mitochondrial electron transport chains tunes T cell activation threshold in tumors
title Chemical augmentation of mitochondrial electron transport chains tunes T cell activation threshold in tumors
title_full Chemical augmentation of mitochondrial electron transport chains tunes T cell activation threshold in tumors
title_fullStr Chemical augmentation of mitochondrial electron transport chains tunes T cell activation threshold in tumors
title_full_unstemmed Chemical augmentation of mitochondrial electron transport chains tunes T cell activation threshold in tumors
title_short Chemical augmentation of mitochondrial electron transport chains tunes T cell activation threshold in tumors
title_sort chemical augmentation of mitochondrial electron transport chains tunes t cell activation threshold in tumors
topic Basic Tumor Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8814813/
https://www.ncbi.nlm.nih.gov/pubmed/35115364
http://dx.doi.org/10.1136/jitc-2021-003958
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