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Transgelin 2 guards T cell lipid metabolism and anti-tumor function

ABSTRACT: Mounting effective immunity against pathogens and tumors relies on the successful metabolic programming of T cells by extracellular fatty acids. Fatty acid-binding protein 5 (FABP5) plays a key role in this process by coordinating the efficient import and trafficking of lipids that fuel mitochondrial respiration to sustain the bioenergetic requirements of protective CD8+ T cells. Importantly, however, the mechanisms governing this immunometabolic axis remain unexplored. Here, we report that the cytoskeletal organizer Transgelin 2 (TAGLN2) is necessary for optimal fatty acid uptake, mitochondrial respiration, and anti-cancer function in CD8+ T cells. We found that TAGLN2 interacts with FABP5, enabling its cell surface localization and function in activated CD8+ T cells. Analysis of ovarian cancer specimens revealed that endoplasmic reticulum (ER) stress responses elicited by the tumor microenvironment repress TAGLN2 in infiltrating CD8+ T cells, thereby enforcing their dysfunctional state. Restoring TAGLN2 expression in ER-stressed CD8+ T cells bolstered their lipid uptake, mitochondrial respiration, and cytotoxic capacity. Accordingly, chimeric antigen receptor T cells overexpressing TAGLN2 bypassed the detrimental effects of tumor-induced ER stress and demonstrated superior therapeutic efficacy in mice with metastatic ovarian cancer. Our study unveils the role of cytoskeletal TAGLN2 in T cell lipid metabolism and highlights the potential to enhance cellular immunotherapy in solid malignancies by preserving the TAGLN2-FABP5 axis.

ORGANISM(S): Mus musculus

PROVIDER: GSE248595 | GEO | 2024/12/31

REPOSITORIES: GEO

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Project description:Differential susceptibility to recurrent infection and exacerbation in COPD is not well understood. Here we investigated the potential impact of genetic variation in Fatty Acid Binding Protein 5 (FABP5), a metabolic regulator we previously demonstrated to be downregulated in COPD and further downregulated in patients reporting one or more exacerbation. Through negative binomial analysis of the COPDGene SNP dataset, we identified 5 novel linked single nucleotide polymorphisms (SNPs) across the FABP5 locus that were significantly associated with severe exacerbations in a Non-Hispanic White cohort (rs4338057, rs12549270, rs202275, rs202277, and rs202279). We integrated multiple sources of previously published data to prioritize SNPs most likely to exert regulatory function. Ultimately, rs202275 emerged as the lead candidate due to unique alignment with the loading site of a bidirectional RNA Pol II signature of active enhancer utilization in our recently published patient-derived airway epithelial PRO-seq dataset, suggesting a critical regulatory role for the region harboring this variant. Using Micro-C genome-wide chromosome conformation capture, we found that the region harboring rs202275 makes three-dimensional physical contacts with the FABP5 transcription start site (TSS), suggesting the SNP region could regulate FABP5 transcription through a looping mechanism. To examine SNP function, we analyzed previously deposited gene-array data (GEO Accession #GSE42057) from peripheral blood mononuclear cell (PBMC) samples and found that COPD patients carrying the rs202275 risk allele (T) express significantly lower levels of FABP5 compared to non-carrier patients. Seahorse real-time mitochondrial respiration assays in freshly isolated PBMCs further revealed disrupted oxidative phosphorylation in cells from patients carrying the rs202275 risk allele. As macrophage polarization from pro-inflammatory toward pro-resolving phenotype is dependent on oxidative metabolism, the functional impact of the rs202275 risk allele and associated reduction in FABP5 transcription may contribute to increased or prolonged systemic inflammation, thereby increasing susceptibility to exacerbation in COPD.

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Transgelin 2 guards T cell lipid metabolism and anti-tumor function

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