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

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  • Jacqueline A. Turner

    (University of Colorado School of Medicine, Anschutz Medical Campus
    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)

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.

Suggested Citation

  • 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, 2023. "Lysophosphatidic acid modulates CD8 T cell immunosurveillance and metabolism to impair anti-tumor immunity," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38933-4
    DOI: 10.1038/s41467-023-38933-4
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