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1.
Cancer Res ; 82(10): 1969-1990, 2022 05 16.
Article in English | MEDLINE | ID: mdl-35404405

ABSTRACT

Mitochondria and endoplasmic reticulum (ER) share structural and functional networks and activate well-orchestrated signaling processes to shape cells' fate and function. While persistent ER stress (ERS) response leads to mitochondrial collapse, moderate ERS promotes mitochondrial function. Strategies to boost antitumor T-cell function by targeting ER-mitochondria cross-talk have not yet been exploited. Here, we used carbon monoxide (CO), a short-lived gaseous molecule, to test whether engaging moderate ERS conditions can improve mitochondrial and antitumor functions in T cells. In melanoma antigen-specific T cells, CO-induced transient activation of ERS sensor protein kinase R-like endoplasmic reticulum kinase (PERK) significantly increased antitumor T-cell function. Furthermore, CO-induced PERK activation temporarily halted protein translation and induced protective autophagy, including mitophagy. The use of LC3-GFP enabled differentiation between the cells that prepare themselves to undergo active autophagy (LC3-GFPpos) and those that fail to enter the process (LC3-GFPneg). LC3-GFPpos T cells showed strong antitumor potential, whereas LC3-GFPneg cells exhibited a T regulatory-like phenotype, harbored dysfunctional mitochondria, and accumulated abnormal metabolite content. These anomalous ratios of metabolites rendered the cells with a hypermethylated state and distinct epigenetic profile, limiting their antitumor activity. Overall, this study shows that ERS-activated autophagy pathways modify the mitochondrial function and epigenetically reprogram T cells toward a superior antitumor phenotype to achieve robust tumor control. SIGNIFICANCE: Transient activation of ER stress with carbon monoxide drives mitochondrial biogenesis and protective autophagy that elicits superior antitumor T-cell function, revealing an approach to improving adoptive cell efficacy therapy.


Subject(s)
Carbon Monoxide , eIF-2 Kinase , Apoptosis , Autophagy , Carbon Monoxide/pharmacology , Endoplasmic Reticulum Stress/physiology , Humans , T-Lymphocytes/metabolism , eIF-2 Kinase/genetics , eIF-2 Kinase/metabolism
2.
Cell Rep ; 35(5): 109076, 2021 05 04.
Article in English | MEDLINE | ID: mdl-33951438

ABSTRACT

We lack a mechanistic understanding of aging-mediated changes in mitochondrial bioenergetics and lipid metabolism that affect T cell function. The bioactive sphingolipid ceramide, induced by aging stress, mediates mitophagy and cell death; however, the aging-related roles of ceramide metabolism in regulating T cell function remain unknown. Here, we show that activated T cells isolated from aging mice have elevated C14/C16 ceramide accumulation in mitochondria, generated by ceramide synthase 6, leading to mitophagy/mitochondrial dysfunction. Mechanistically, aging-dependent mitochondrial ceramide inhibits protein kinase A, leading to mitophagy in activated T cells. This aging/ceramide-dependent mitophagy attenuates the antitumor functions of T cells in vitro and in vivo. Also, inhibition of ceramide metabolism or PKA activation by genetic and pharmacologic means prevents mitophagy and restores the central memory phenotype in aging T cells. Thus, these studies help explain the mechanisms behind aging-related dysregulation of T cells' antitumor activity, which can be restored by inhibiting ceramide-dependent mitophagy.


Subject(s)
Aging , Ceramides/metabolism , Mitochondria/metabolism , T-Lymphocytes/metabolism , Animals , Humans , Mice , Signal Transduction
3.
Cell Rep ; 28(7): 1879-1893.e7, 2019 08 13.
Article in English | MEDLINE | ID: mdl-31412253

ABSTRACT

Sphingosine 1-phosphate (S1P), a bioactive lysophospholipid generated by sphingosine kinase 1 (SphK1), regulates lymphocyte egress into circulation via S1P receptor 1 (S1PR1) signaling, and it controls the differentiation of regulatory T cells (Tregs) and T helper-17 cells. However, the mechanisms by which receptor-independent SphK1-mediated intracellular S1P levels modulate T cell functionality remains unknown. We show here that SphK1-deficient T cells maintain central memory phenotype and exhibit higher mitochondrial respiration and reduced differentiation to Tregs. Mechanistically, we discovered a direct correlation between SphK1-generated S1P and lipid transcription factor PPARγ (peroxisome proliferator-activated receptor gamma) activity, which in turn regulates lipolysis in T cells. Genetic and pharmacologic inhibition of SphK1 improved metabolic fitness and anti-tumor activity of T cells against murine melanoma. Further, inhibition of SphK1 and PD1 together led to improved control of melanoma. Overall, these data highlight the clinical potential of limiting SphK1/S1P signaling for enhancing anti-tumor-adoptive T cell therapy.


Subject(s)
Cellular Reprogramming , Gene Expression Regulation, Neoplastic , Lysophospholipids/metabolism , Melanoma, Experimental/pathology , PPAR gamma/physiology , Phosphotransferases (Alcohol Group Acceptor)/physiology , Sphingosine/analogs & derivatives , T-Lymphocytes/immunology , Animals , Female , Male , Melanoma, Experimental/immunology , Melanoma, Experimental/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Oxidative Phosphorylation , Receptors, Lysosphingolipid/metabolism , Signal Transduction , Sphingosine/metabolism , T-Lymphocytes/metabolism
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