Reprogramming lipid metabolism prevents effector T cell senescence and enhances tumor immunotherapy

Abstract

The functional state of T cells is a key determinant for effective antitumor immunity and immunotherapy. Cellular metabolism, including lipid metabolism, controls T cell differentiation, survival, and effector functions. Here, we report that development of T cell senescence driven by both malignant tumor cells and regulatory T cells is a general feature in cancers. Senescent T cells have active glucose metabolism but exhibit unbalanced lipid metabolism. This unbalanced lipid metabolism results in changes of expression of lipid metabolic enzymes, which, in turn, alters lipid species and accumulation of lipid droplets in T cells. Tumor cells and Treg cells drove elevated expression of group IVA phospholipase A2, which, in turn, was responsible for the altered lipid metabolism and senescence induction observed in T cells. Mitogen-activated protein kinase signaling and signal transducer and activator of transcription signaling coordinately control lipid metabolism and group IVA phospholipase A2 activity in responder T cells during T cell senescence. Inhibition of group IVA phospholipase A2 reprogrammed effector T cell lipid metabolism, prevented T cell senescence in vitro, and enhanced antitumor immunity and immunotherapy efficacy in mouse models of melanoma and breast cancer in vivo. Together, these findings identify mechanistic links between T cell senescence and regulation of lipid metabolism in the tumor microenvironment and provide a new target for tumor immunotherapy.

Pyroptosis, metabolism, and tumor immune microenvironment

“… 278 , 279 , 280 , 281 , 282 Besides, elevated lipid metabolism and glucose/amino acid dearth also increase the production of reactive ROS and suppressive epigenetic modifications in T cells. 280 , 283 The metabolic characteristics of TME could further damage antitumor immunity and accelerate malignant progression. Moreover, obesity and other diseases caused by metabolism dysregulation are accompanied by inflammation to different degrees, which may induce a tendency toward tumor development if the inflammation exists for a long time.…”

“…However, the metabolic demands of tumors lead to severe dysfunction and abnormal differentiation in cytotoxic immune cells, including T cells and NK cells, which principally use glucose by glycolysis and mitochondrial oxidative phosphorylation 278–282 . Besides, elevated lipid metabolism and glucose/amino acid dearth also increase the production of reactive ROS and suppressive epigenetic modifications in T cells 280,283 . The metabolic characteristics of TME could further damage antitumor immunity and accelerate malignant progression.…”

A Novel Risk Model Based on Lipid Metabolism-Associated Genes Predicts Prognosis and Indicates Immune Microenvironment in Breast Cancer

“…The anti-tumor role of T cells may be enhanced by cholesterol; however, its role is negatively regulated by liver X receptors in the oxysterol-abundant TM ( Matsushita et al, 2021 ). A recent study demonstrated that lipid metabolism reprograming, triggered by the unbalanced lipid metabolism in senescent T cells, prevented the senescence of effector T cells ( Liu X. et al, 2021 ) and enhanced the functional specialization of regulatory T cells in cancers ( Lim et al, 2021 ). Lipid accumulation in the dendritic cells damaged their anti-tumor functions, as the affected cells could not effectively present tumor-associated antigens ( Herber et al, 2010 ).…”

The Comprehensive “Omics” Approach from Metabolomics to Advanced Omics for Development of Immune Checkpoint Inhibitors: Potential Strategies for Next Generation of Cancer Immunotherapy

“…Liu et al reported an association between lipid metabolism and T-cell senescence, suggesting that reprogrammed lipid metabolism was triggered by the upregulation of PLA2G4A in cancer cells and regulatory T-cells. Using melanoma and breast cancer in vivo models, they demonstrated enhanced therapeutic efficacy following inhibition of PLA2G4A [82]. Moreover, another study identified the negative correlation between response to tumor-infiltrating lymphocyte (TIL) therapy and upregulation of Sirt2 in human TILs.…”