Despite the approval of several anti-angiogenic therapies, clinical results remain unsatisfactory, and transient benefits are followed by rapid tumor recurrence. Here, we demonstrate potent ...anti-angiogenic efficacy of the multi-kinase inhibitors nintedanib and sunitinib in a mouse model of breast cancer. However, after an initial regression, tumors resume growth in the absence of active tumor angiogenesis. Gene expression profiling of tumor cells reveals metabolic reprogramming toward anaerobic glycolysis. Indeed, combinatorial treatment with a glycolysis inhibitor (3PO) efficiently inhibits tumor growth. Moreover, tumors establish metabolic symbiosis, illustrated by the differential expression of MCT1 and MCT4, monocarboxylate transporters active in lactate exchange in glycolytic tumors. Accordingly, genetic ablation of MCT4 expression overcomes adaptive resistance against anti-angiogenic therapy. Hence, targeting metabolic symbiosis may be an attractive avenue to avoid resistance development to anti-angiogenic therapy in patients.
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•Tumors can escape anti-angiogenic therapy with multi-kinase inhibitors•A glycolytic shift underlies resistance against multi-kinase inhibitors•Metabolic symbiosis between hypoxic and oxygenated cells inspires therapy resistance•Inhibition of glycolysis or lactate export collapses metabolic symbiosis
Pisarsky et al. examine the role of metabolic symbiosis as a mechanism underlying evasive resistance to anti-angiogenic therapy by the multi-kinase inhibitors nintedanib and sunitinib. Inhibition of glycolysis or genetic ablation of the lactate exporter MCT4 in tumor cells disrupts metabolic symbiosis, overrides therapy resistance, and suppresses tumor growth.
Dynamic, coordinated changes in metabolic pathway activity underpin the protective and inflammatory activity of T cells, through provision of energy and biosynthetic precursors for effector ...functions, as well as direct effects of metabolic enzymes, intermediates and end-products on signaling pathways and transcriptional mechanisms. Consequently, it has become increasingly clear that the metabolic status of the tissue microenvironment directly influences T cell activity, with changes in nutrient and/or metabolite abundance leading to dysfunctional T cell metabolism and interlinked immune function. Emerging evidence now indicates that additional signals are integrated by T cells to determine their overall metabolic phenotype, including those arising from interaction with cytokines and hormones in their environment. The impact of these on T cell metabolism, the mechanisms involved and the pathological implications are discussed in this review article.
Whether screening the metabolic activity of immune cells facilitates discovery of molecular pathology remains unknown. Here we prospectively screened the extracellular acidification rate as a measure ...of glycolysis and the oxygen consumption rate as a measure of mitochondrial respiration in B cells from patients with primary antibody deficiency. The highest oxygen consumption rate values were detected in three study participants with persistent polyclonal B cell lymphocytosis (PPBL). Exome sequencing identified germline mutations in SDHA, which encodes succinate dehydrogenase subunit A, in all three patients with PPBL. SDHA gain-of-function led to an accumulation of fumarate in PPBL B cells, which engaged the KEAP1-Nrf2 system to drive the transcription of genes encoding inflammatory cytokines. In a single patient trial, blocking the activity of the cytokine interleukin-6 in vivo prevented systemic inflammation and ameliorated clinical disease. Overall, our study has identified pathological mitochondrial retrograde signaling as a disease modifier in primary antibody deficiency.
Augmented T cell function leading to host damage in autoimmunity is supported by metabolic dysregulation, making targeting immunometabolism an attractive therapeutic avenue. Canagliflozin, a type 2 ...diabetes drug, is a sodium glucose co-transporter 2 (SGLT2) inhibitor with known off-target effects on glutamate dehydrogenase and complex I. However, the effects of SGLT2 inhibitors on human T cell function have not been extensively explored. Here, we show that canagliflozin-treated T cells are compromised in their ability to activate, proliferate, and initiate effector functions. Canagliflozin inhibits T cell receptor signaling, impacting on ERK and mTORC1 activity, concomitantly associated with reduced c-Myc. Compromised c-Myc levels were encapsulated by a failure to engage translational machinery resulting in impaired metabolic protein and solute carrier production among others. Importantly, canagliflozin-treated T cells derived from patients with autoimmune disorders impaired their effector function. Taken together, our work highlights a potential therapeutic avenue for repurposing canagliflozin as an intervention for T cell-mediated autoimmunity.
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•Canagliflozin (cana) inhibits human T cell effector function•Cana compromises T cell receptor signaling•Cana impairs the activity of ERK, mTORC, and Myc, preventing metabolic rewiring•Cana impairs the effector function of T cells derived from patients with autoimmunity
Jenkins et al. report that the SGLT2 inhibitor, canagliflozin, compromises human T cell effector function. Canagliflozin prevents T cell activation and proliferation by antagonizing TCR signaling, impairing the activity of c-Myc, leading to a failure to engage in metabolic rewiring. In vitro, canagliflozin impairs T cell function in patients with autoimmunity.
Vitamin D has well documented effects on calcium homeostasis and bone metabolism but recent studies suggest a much broader role for this secosteroid in human health. Key components of the vitamin D ...system, notably the vitamin D receptor (VDR) and the vitamin D activating enzyme (1α-hydroxylase), are present in a wide array of tissues, notably macrophages, dendritic cells and T lymphocytes (T cells) from the immune system. Thus, serum 25-hydroxyvitamin D (25D) can be converted to hormonal 1,25-dihydroxyvitamin D (1,25D) within immune cells, and then interact with VDR and promote transcriptional and epigenomic responses in the same or neighbouring cells. These intracrine and paracrine effects of 1,25D have been shown to drive antibacterial or antiviral innate responses, as well as attenuating inflammatory T cell adaptive immunity. Beyond these mechanistic observations, association studies have reported correlation between low serum 25D levels and the risk and severity of human immune disorders including autoimmune diseases such as inflammatory bowel disease, multiple sclerosis, type 1 diabetes and rheumatoid arthritis. The proposed explanation for this is that decreased availability of 25D compromises immune cell synthesis of 1,25D leading to impaired innate immunity and over-exuberant inflammatory adaptive immunity. The aim of the current review is to explore the mechanistic basis for immunomodulatory effects of 25D and 1,25D in greater detail with specific emphasis on how vitamin D-deficiency (low serum levels of 25D) may lead to dysregulation of macrophage, dendritic cell and T cell function, and increase risk of inflammatory autoimmune disease.
T lymphocytes are a critical component of the adaptive immune system, with key roles in the immune response to infection and cancer. Their activity is fundamentally underpinned by dynamic, regulated ...changes in their metabolism. This ensures adequate availability of energy and biosynthetic precursors for clonal expansion and effector function, and also directly regulates cell signaling, gene transcription, and protein translation. In health, distinct T cells subtypes demonstrate differences in intrinsic metabolic capacity which correlate with their specialized immune functions. In disease, T cells with impaired immune function appear to be likewise metabolically impaired. Furthermore, diseased tissue environments—through inadequate provision of nutrients and oxygen, or accumulation of metabolic intermediates, end-products, and cytokines- can impose metabolic insufficiency upon these cells, and further compound intrinsic impairments. These intrinsic and extrinsic determinants of T cell metabolism and their potential compound effects, together with the mechanisms involved form the subject of this review. We will also discuss how dysfunctional metabolic pathways may be therapeutically targeted to restore normal T cell function in disease.
T-cell acute lymphoblastic leukemia (T-ALL) is a cancer of the immune system. Approximately 20% of paediatric and 50% of adult T-ALL patients have refractory disease or relapse and die from the ...disease. To improve patient outcome new therapeutics are needed. With the aim to identify new therapeutic targets, we combined the analysis of T-ALL gene expression and metabolism to identify the metabolic adaptations that T-ALL cells exhibit. We found that glutamine uptake is essential for T-ALL proliferation. Isotope tracing experiments showed that glutamine fuels aspartate synthesis through the TCA cycle and that glutamine and glutamine-derived aspartate together supply three nitrogen atoms in purines and all but one atom in pyrimidine rings. We show that the glutamate-aspartate transporter EAAT1 (SLC1A3), which is normally expressed in the central nervous system, is crucial for glutamine conversion to aspartate and nucleotides and that T-ALL cell proliferation depends on EAAT1 function. Through this work, we identify EAAT1 as a novel therapeutic target for T-ALL treatment.
The ZFP36 family of RNA-binding proteins acts post-transcriptionally to repress translation and promote RNA decay. Studies of genes and pathways regulated by the ZFP36 family in CD4
T cells have ...focussed largely on cytokines, but their impact on metabolic reprogramming and differentiation is unclear. Using CD4
T cells lacking Zfp36 and Zfp36l1, we combined the quantification of mRNA transcription, stability, abundance and translation with crosslinking immunoprecipitation and metabolic profiling to determine how they regulate T cell metabolism and differentiation. Our results suggest that ZFP36 and ZFP36L1 act directly to limit the expression of genes driving anabolic processes by two distinct routes: by targeting transcription factors and by targeting transcripts encoding rate-limiting enzymes. These enzymes span numerous metabolic pathways including glycolysis, one-carbon metabolism and glutaminolysis. Direct binding and repression of transcripts encoding glutamine transporter SLC38A2 correlated with increased cellular glutamine content in ZFP36/ZFP36L1-deficient T cells. Increased conversion of glutamine to α-ketoglutarate in these cells was consistent with direct binding of ZFP36/ZFP36L1 to Gls (encoding glutaminase) and Glud1 (encoding glutamate dehydrogenase). We propose that ZFP36 and ZFP36L1 as well as glutamine and α-ketoglutarate are limiting factors for the acquisition of the cytotoxic CD4
T cell fate. Our data implicate ZFP36 and ZFP36L1 in limiting glutamine anaplerosis and differentiation of activated CD4
T cells, likely mediated by direct binding to transcripts of critical genes that drive these processes.
Background:
Vitamin D upregulates anti-inflammatory and antimicrobial pathways that promote respiratory health. Vitamin D synthesis is initiated following skin exposure to sunlight, however ...nutritional supplementation can be required to address deficiency, for example during the winter months or due to cultural constraints. We recently reported that 1α,25-dihydroxyvitamin D3 (1,25(OH)
2
D3) treatment induced alpha-1 antitrypsin (AAT) expression in CD4+, but not CD8+ T cells, with evidence supporting an immunoregulatory role.
Research Question:
To understand the relationship between vitamin D, lung AAT levels and T lymphocytes further we investigated whether TGF-β is required as a co-factor for 1,25(OH)
2
D3-induced upregulation of AAT by vitamin D in CD8+ T cells
in vitro
and correlated circulating vitamin D levels with lung AAT levels
in vivo
.
Results:
1,25(OH)
2
D3 in combination with TGF-β1 increased AAT expression by CD8+ T cells, as well as
VDR
and
RXR
α gene expression, which may partly explain the requirement for TGF-β. CD4+ T cells may also require autocrine stimulation with TGF-β as a co-factor since 1,25(OH)
2
D3 was associated with increased TGF-β bioactivity and neutralisation of TGF-β partially abrogated 1,25(OH)
2
D3-induced
SERPINA1
gene expression. Neither CD4+ nor CD8+ T cells responded to the circulating vitamin D precursor, 25-hydroxyvitamin D3 for induction of
SERPINA1
, suggesting that local generation of 1,25(OH)
2
D3 is required. Transcriptional gene profiling studies previously demonstrated that human bronchial epithelial cells rapidly increased TGF-β2 gene expression in response to 1,25(OH)
2
D3. Here, human epithelial cells responded to precursor 25(OH)D3 to increase bioactive TGF-β synthesis. CD8+ T cells responded comparably to TGF-β1 and TGF-β2 to increase 1,25(OH)
2
D3-induced AAT. However, CD8+ T cells from adults with AAT-deficiency, homozygous for the Z allele of
SERPINA1
, were unable to mount this response. AAT levels in the airways of children with asthma and controls correlated with circulating 25(OH)D3.
Conclusions:
Vitamin D increases AAT expression in human T cells and this response is impaired in T cells from individuals homozygous for the Z allele of
SERPINA1
in a clinic population. Furthermore, a correlation between circulating vitamin D and airway AAT is reported. We propose that vitamin D-induced AAT contributes to local immunomodulation and airway health effects previously attributed to vitamin D.
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