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Tumor cell–derived spermidine is an oncometabolite that suppresses TCR clustering for intratumoral CD8(+) T cell activation

The activation and expansion of T cells that recognize cancer cells is an essential aspect to antitumor immunity. Tumors may escape destruction by the immune system through ectopic expression of inhibitory immune ligands typically exemplified by the PD-L1/PD-1 pathway. Here, we reveal another facet...

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Autores principales: Hibino, Sana, Eto, Shotaro, Hangai, Sho, Endo, Keiko, Ashitani, Sanae, Sugaya, Maki, Osawa, Tsuyoshi, Soga, Tomoyoshi, Taniguchi, Tadatsugu, Yanai, Hideyuki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10268234/
https://www.ncbi.nlm.nih.gov/pubmed/37276392
http://dx.doi.org/10.1073/pnas.2305245120
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author Hibino, Sana
Eto, Shotaro
Hangai, Sho
Endo, Keiko
Ashitani, Sanae
Sugaya, Maki
Osawa, Tsuyoshi
Soga, Tomoyoshi
Taniguchi, Tadatsugu
Yanai, Hideyuki
author_facet Hibino, Sana
Eto, Shotaro
Hangai, Sho
Endo, Keiko
Ashitani, Sanae
Sugaya, Maki
Osawa, Tsuyoshi
Soga, Tomoyoshi
Taniguchi, Tadatsugu
Yanai, Hideyuki
author_sort Hibino, Sana
collection PubMed
description The activation and expansion of T cells that recognize cancer cells is an essential aspect to antitumor immunity. Tumors may escape destruction by the immune system through ectopic expression of inhibitory immune ligands typically exemplified by the PD-L1/PD-1 pathway. Here, we reveal another facet of tumor evasion from T cell surveillance. By secretome profiling of necrotic tumor cells, we identified an oncometabolite spermidine as a unique inhibitor of T cell receptor (TCR) signaling. Mechanistically, spermidine causes the downregulation of the plasma membrane cholesterol levels, resulting in the suppression of TCR clustering. Using syngeneic mouse models, we show that spermidine is abundantly detected in the tumor immune microenvironment (TIME) and that administration of the polyamine synthesis inhibitor effectively enhanced CD8(+) T cell–dependent antitumor responses. Further, the combination of the polyamine synthesis inhibitor with anti-PD-1 immune checkpoint antibody resulted in a much stronger antitumor immune response. This study reveals an aspect of immunosuppressive TIME, wherein spermidine functions as a metabolic T cell checkpoint that may offer a unique approach for promoting tumor immunotherapy.
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spelling pubmed-102682342023-12-05 Tumor cell–derived spermidine is an oncometabolite that suppresses TCR clustering for intratumoral CD8(+) T cell activation Hibino, Sana Eto, Shotaro Hangai, Sho Endo, Keiko Ashitani, Sanae Sugaya, Maki Osawa, Tsuyoshi Soga, Tomoyoshi Taniguchi, Tadatsugu Yanai, Hideyuki Proc Natl Acad Sci U S A Biological Sciences The activation and expansion of T cells that recognize cancer cells is an essential aspect to antitumor immunity. Tumors may escape destruction by the immune system through ectopic expression of inhibitory immune ligands typically exemplified by the PD-L1/PD-1 pathway. Here, we reveal another facet of tumor evasion from T cell surveillance. By secretome profiling of necrotic tumor cells, we identified an oncometabolite spermidine as a unique inhibitor of T cell receptor (TCR) signaling. Mechanistically, spermidine causes the downregulation of the plasma membrane cholesterol levels, resulting in the suppression of TCR clustering. Using syngeneic mouse models, we show that spermidine is abundantly detected in the tumor immune microenvironment (TIME) and that administration of the polyamine synthesis inhibitor effectively enhanced CD8(+) T cell–dependent antitumor responses. Further, the combination of the polyamine synthesis inhibitor with anti-PD-1 immune checkpoint antibody resulted in a much stronger antitumor immune response. This study reveals an aspect of immunosuppressive TIME, wherein spermidine functions as a metabolic T cell checkpoint that may offer a unique approach for promoting tumor immunotherapy. National Academy of Sciences 2023-06-05 2023-06-13 /pmc/articles/PMC10268234/ /pubmed/37276392 http://dx.doi.org/10.1073/pnas.2305245120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Hibino, Sana
Eto, Shotaro
Hangai, Sho
Endo, Keiko
Ashitani, Sanae
Sugaya, Maki
Osawa, Tsuyoshi
Soga, Tomoyoshi
Taniguchi, Tadatsugu
Yanai, Hideyuki
Tumor cell–derived spermidine is an oncometabolite that suppresses TCR clustering for intratumoral CD8(+) T cell activation
title Tumor cell–derived spermidine is an oncometabolite that suppresses TCR clustering for intratumoral CD8(+) T cell activation
title_full Tumor cell–derived spermidine is an oncometabolite that suppresses TCR clustering for intratumoral CD8(+) T cell activation
title_fullStr Tumor cell–derived spermidine is an oncometabolite that suppresses TCR clustering for intratumoral CD8(+) T cell activation
title_full_unstemmed Tumor cell–derived spermidine is an oncometabolite that suppresses TCR clustering for intratumoral CD8(+) T cell activation
title_short Tumor cell–derived spermidine is an oncometabolite that suppresses TCR clustering for intratumoral CD8(+) T cell activation
title_sort tumor cell–derived spermidine is an oncometabolite that suppresses tcr clustering for intratumoral cd8(+) t cell activation
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10268234/
https://www.ncbi.nlm.nih.gov/pubmed/37276392
http://dx.doi.org/10.1073/pnas.2305245120
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