Title: Oxidized Lipids and CD36-Mediated Lipid Peroxidation in CD8 T Cells Suppress Anti-Tumor Immune Responses

Accession Number: GSE171194

Link to Dataset: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE171194

Repository: Gene Expression Omnibus (GEO)

Data Type(s): Gene Expression

Experiment Type(s): Expression profiling by high throughput sequencing

Organism(s): Mus musculus

Summary: T cell metabolic fitness plays a pivotal role in anti-tumor immunity and metabolic deregulation causes T cell dysfunction in cancer. We identify that CD36 limits anti-tumor CD8+ T cell effector functions through lipid peroxidation. In murine tumors, oxidized phospholipids (OxPLs) were highly abundant and CD8+ TILs increased uptake and accumulation of lipids and lipid peroxidation. Functionally ‘exhausted’ CD8+ TILs increased CD36 expression and CD36-deficient CD8+ TILs had more robust anti-tumor activity and cytokine production than wild-type cells. We further show that CD36 promotes uptake of oxidized low-density lipoproteins (OxLDL), induces lipid peroxidation in CD8+ TILs, and enhances p38 kinase phosphorylation. Moreover, we found that OxLDL inhibits CD8+ T cell functions in a CD36/p38-dependent manner. Furthermore, glutathione peroxidase 4 (GPX4) over-expression lowers lipid peroxidation and restores functionalities in CD8+ TILs. These results define a key role for an oxidized lipid-CD36-p38 axis in promoting intratumoral CD8+ T cell dysfunction.

Publication(s) associated with this dataset:

• Xu SA, Chaudhary O, Rodriguez-Morales P, Sun X, Chen D, Zappasodi R, Xu Z, Pinto AF, Williams A, Schulze I, Farsakoglu Y, Varanasi SK, Low JS, Tang W, Wang H, McDonald B, Tripple V, Downes M, Evans RM, Abumrad NA, Merghoub T, Wolchok JD, Shokhirev MN, Ho P, Witztum JL, Emu B, Cui G, Kaech SM. 2021. Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8(+) T cells in tumors. Immunity 54:1561-1577. doi:10.1016/j.immuni.2021.05.003 PMID:34102100

Project(s) associated with this dataset:

• University of California-San Diego: Nuclear Receptor Mediated Epigenetic and Immune Cell Changes in Liver Fibrosis Resulting From Toxicant Exposure