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Lysophosphatidic acid modulates CD8 T cell immunosurveillance and metabolism to impair anti-tumor immunity
Lysophosphatidic acid (LPA) is a bioactive lipid which increases in concentration locally and systemically across different cancer types. Yet, the exact mechanism(s) of how LPA affects CD8 T cell immunosurveillance during tumor progression remain unknown. We show LPA receptor (LPAR) signaling by CD8...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10239450/ https://www.ncbi.nlm.nih.gov/pubmed/37270644 http://dx.doi.org/10.1038/s41467-023-38933-4 |
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author | Turner, Jacqueline A. Fredrickson, Malia A. D’Antonio, Marc Katsnelson, Elizabeth MacBeth, Morgan Van Gulick, Robert Chimed, Tugs-Saikhan McCarter, Martin D’Alessandro, Angelo Robinson, William A. Couts, Kasey L. Pelanda, Roberta Klarquist, Jared Tobin, Richard P. Torres, Raul M. |
author_facet | Turner, Jacqueline A. Fredrickson, Malia A. D’Antonio, Marc Katsnelson, Elizabeth MacBeth, Morgan Van Gulick, Robert Chimed, Tugs-Saikhan McCarter, Martin D’Alessandro, Angelo Robinson, William A. Couts, Kasey L. Pelanda, Roberta Klarquist, Jared Tobin, Richard P. Torres, Raul M. |
author_sort | Turner, Jacqueline A. |
collection | PubMed |
description | Lysophosphatidic acid (LPA) is a bioactive lipid which increases in concentration locally and systemically across different cancer types. Yet, the exact mechanism(s) of how LPA affects CD8 T cell immunosurveillance during tumor progression remain unknown. We show LPA receptor (LPAR) signaling by CD8 T cells promotes tolerogenic states via metabolic reprogramming and potentiating exhaustive-like differentiation to modulate anti-tumor immunity. We found LPA levels predict response to immunotherapy and Lpar5 signaling promotes cellular states associated with exhausted phenotypes on CD8 T cells. Importantly, we show that Lpar5 regulates CD8 T cell respiration, proton leak, and reactive oxygen species. Together, our findings reveal that LPA serves as a lipid-regulated immune checkpoint by modulating metabolic efficiency through LPAR5 signaling on CD8 T cells. Our study offers key insights into the mechanisms governing adaptive anti-tumor immunity and demonstrates LPA could be exploited as a T cell directed therapy to improve dysfunctional anti-tumor immunity. |
format | Online Article Text |
id | pubmed-10239450 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-102394502023-06-05 Lysophosphatidic acid modulates CD8 T cell immunosurveillance and metabolism to impair anti-tumor immunity Turner, Jacqueline A. Fredrickson, Malia A. D’Antonio, Marc Katsnelson, Elizabeth MacBeth, Morgan Van Gulick, Robert Chimed, Tugs-Saikhan McCarter, Martin D’Alessandro, Angelo Robinson, William A. Couts, Kasey L. Pelanda, Roberta Klarquist, Jared Tobin, Richard P. Torres, Raul M. Nat Commun Article Lysophosphatidic acid (LPA) is a bioactive lipid which increases in concentration locally and systemically across different cancer types. Yet, the exact mechanism(s) of how LPA affects CD8 T cell immunosurveillance during tumor progression remain unknown. We show LPA receptor (LPAR) signaling by CD8 T cells promotes tolerogenic states via metabolic reprogramming and potentiating exhaustive-like differentiation to modulate anti-tumor immunity. We found LPA levels predict response to immunotherapy and Lpar5 signaling promotes cellular states associated with exhausted phenotypes on CD8 T cells. Importantly, we show that Lpar5 regulates CD8 T cell respiration, proton leak, and reactive oxygen species. Together, our findings reveal that LPA serves as a lipid-regulated immune checkpoint by modulating metabolic efficiency through LPAR5 signaling on CD8 T cells. Our study offers key insights into the mechanisms governing adaptive anti-tumor immunity and demonstrates LPA could be exploited as a T cell directed therapy to improve dysfunctional anti-tumor immunity. Nature Publishing Group UK 2023-06-03 /pmc/articles/PMC10239450/ /pubmed/37270644 http://dx.doi.org/10.1038/s41467-023-38933-4 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Turner, Jacqueline A. Fredrickson, Malia A. D’Antonio, Marc Katsnelson, Elizabeth MacBeth, Morgan Van Gulick, Robert Chimed, Tugs-Saikhan McCarter, Martin D’Alessandro, Angelo Robinson, William A. Couts, Kasey L. Pelanda, Roberta Klarquist, Jared Tobin, Richard P. Torres, Raul M. Lysophosphatidic acid modulates CD8 T cell immunosurveillance and metabolism to impair anti-tumor immunity |
title | Lysophosphatidic acid modulates CD8 T cell immunosurveillance and metabolism to impair anti-tumor immunity |
title_full | Lysophosphatidic acid modulates CD8 T cell immunosurveillance and metabolism to impair anti-tumor immunity |
title_fullStr | Lysophosphatidic acid modulates CD8 T cell immunosurveillance and metabolism to impair anti-tumor immunity |
title_full_unstemmed | Lysophosphatidic acid modulates CD8 T cell immunosurveillance and metabolism to impair anti-tumor immunity |
title_short | Lysophosphatidic acid modulates CD8 T cell immunosurveillance and metabolism to impair anti-tumor immunity |
title_sort | lysophosphatidic acid modulates cd8 t cell immunosurveillance and metabolism to impair anti-tumor immunity |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10239450/ https://www.ncbi.nlm.nih.gov/pubmed/37270644 http://dx.doi.org/10.1038/s41467-023-38933-4 |
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