Lysophosphatidic acid modulates CD8 T cell immunosurveillance and metabolism to impair anti-tumor immunity

Jacqueline A. Turner, Malia A. Fredrickson, Marc D’Antonio, Elizabeth Katsnelson, Morgan MacBeth, Robert Gulick, Tugs-Saikhan Chimed, Martin McCarter, Angelo D’Alessandro, William A. Robinson, Kasey L. Couts, Roberta Pelanda, Jared Klarquist, Richard P. Tobin and Raul M. Torres ()
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Jacqueline A. Turner: University of Colorado School of Medicine, Anschutz Medical Campus
Malia A. Fredrickson: University of Colorado School of Medicine, Anschutz Medical Campus
Marc D’Antonio: University of Colorado School of Medicine, Anschutz Medical Campus
Elizabeth Katsnelson: University of Colorado School of Medicine, Anschutz Medical Campus
Morgan MacBeth: University of Colorado School of Medicine, Anschutz Medical Campus
Robert Gulick: University of Colorado School of Medicine, Anschutz Medical Campus
Tugs-Saikhan Chimed: University of Colorado School of Medicine, Anschutz Medical Campus
Martin McCarter: University of Colorado School of Medicine, Anschutz Medical Campus
Angelo D’Alessandro: University of Colorado School of Medicine, Anschutz Medical Campus
William A. Robinson: University of Colorado School of Medicine, Anschutz Medical Campus
Kasey L. Couts: University of Colorado School of Medicine, Anschutz Medical Campus
Roberta Pelanda: University of Colorado School of Medicine, Anschutz Medical Campus
Jared Klarquist: University of Colorado School of Medicine, Anschutz Medical Campus
Richard P. Tobin: University of Colorado School of Medicine, Anschutz Medical Campus
Raul M. Torres: University of Colorado School of Medicine, Anschutz Medical Campus

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-38933-4

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