We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Lysophosphatidic acid modulates CD8 T cell immunosurveillance and metabolism to impair anti-tumor immunity.
- Authors
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.
- 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. Lysophosphatidic acid is known to increase in concentration in multiple cancer types. Here, the authors show it affects CD8 T cell metabolism, phenotype, and effector functions, and plasma concentrations appear predictive of response to immunotherapy.
- Subjects
LYSOPHOSPHOLIPIDS; CELL metabolism; CD8 antigen; CELL respiration; T cells; IMMUNE checkpoint proteins
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-38933-4