Adiponectin reduces immune checkpoint inhibitor-induced inflammation without blocking anti-tumor immunity.

Immune-related adverse events (irAEs) in cancer patients receiving immune checkpoint inhibitors (ICIs) cause morbidity and necessitate cessation of treatment. Comparing irAE treatments, we find that anti-tumor immunity is preserved in mice after extracorporeal photopheresis (ECP) but reduced with glucocorticosteroids, TNFα blockade, and α4β7-integrin inhibition. Local adiponectin production elicits a tissue-specific effect by reducing pro-inflammatory T cell frequencies in the colon while sparing tumor-specific T cell development.

Androgen receptor drives polyamine synthesis creating a vulnerability for prostate cancer.

Supraphysiological androgen (SPA) treatment can paradoxically restrict growth of castration-resistant prostate cancer with high androgen receptor (AR) activity, which is the basis for use of Bipolar Androgen Therapy (BAT) for patients with this disease. While androgens are widely appreciated to enhance anabolic metabolism, how SPA-mediated metabolic changes alter prostate cancer progression and therapy response is unknown. Here, we report that SPA markedly increased intracellular and secreted polyamines in prostate cancer models.

Please don't go: retinoic acid 'retains' tissue-specific memory.

Tissue-resident memory (T) T cells not only control infection and cancer, but also contribute to inflammatory disease. In a recent study, Obers et al. demonstrate that retinoic acid (RA) and TGF-β direct T residency in mice, with RA uniquely retaining cells in the intestine by limiting migration.

Metabolic adaptations of ILC2 and Th2 cells in type 2 immunity.

Type 2 immune responses play a crucial role in host defense against parasitic infections but can also promote the development of allergies and asthma. This response is orchestrated primarily by group 2 innate lymphoid cells (ILC2) and helper type 2 (Th2) cells, both of which undergo substantial metabolic reprogramming as they transition from resting to activated states. Understanding these metabolic adaptations not only provides insights into the fundamental biology of ILC2 and Th2 cells but also opens up potential therapeutic avenues for the identification of novel metabolic targets that can extend the current treatment regimens for diseases in which type 2 immune responses play pivotal roles.

Glutamine sensing licenses cholesterol synthesis.

The mevalonate pathway produces essential lipid metabolites such as cholesterol. Although this pathway is negatively regulated by metabolic intermediates, little is known of the metabolites that positively regulate its activity. We found that the amino acid glutamine is required to activate the mevalonate pathway.

Landscape of glycolytic metabolites and their regulating proteins in myocardium from human heart failure with preserved ejection fraction.

Aims: Heart failure (HF) with preserved ejection fraction (HFpEF) reflects half of all clinical HF yet has few therapies. Obesity and diabetes are now common comorbidities which have focused attention towards underlying myocardial metabolic defects. The profile of a major metabolic pathway, glycolytic intermediates and their regulating enzymes and ancillary pathways, remains unknown.

Oncogene-induced TIM-3 ligand expression dictates susceptibility to anti-TIM-3 therapy in mice.

Leukemia relapse is a major cause of death after allogeneic hematopoietic cell transplantation (allo-HCT). We tested the potential of targeting T cell (Tc) immunoglobulin and mucin-containing molecule 3 (TIM-3) for improving graft-versus-leukemia (GVL) effects. We observed differential expression of TIM-3 ligands when hematopoietic stem cells overexpressed certain oncogenic-driver mutations.

ATP Citrate Lyase Supports Cardiac Function and NAD+/NADH Balance And Is Depressed in Human Heart Failure.

Background: ATP-citrate lyase (ACLY) converts citrate into acetyl-CoA and oxaloacetate in the cytosol. It plays a prominent role in lipogenesis and fat accumulation coupled to excess glucose, and its inhibition is approved for treating hyperlipidemia. In RNAseq analysis of human failing myocardium, we found ACLY gene expression is reduced; however the impact this might have on cardiac function and/or metabolism has not been previously studied.

Electrostatic encoding of genome organization principles within single native nucleosomes.

The eukaryotic genome, first packed into nucleosomes of about 150 bp around the histone core, is organized into euchromatin and heterochromatin, corresponding to the A and B compartments, respectively. Here, we asked if individual nucleosomes in vivo know where to go. That is, do mono-nucleosomes by themselves contain A/B compartment information, associated with transcription activity, in their biophysical properties? We purified native mono-nucleosomes to high monodispersity and used physiological concentrations of biological polyamines to determine their condensability.

Depressed Proximal Glycolysis in Myocardium Of Human Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) accounts for >50% of all heart failure world-wide and remains a major unmet medical need. The most effective recently approved treatments were first developed for diabetes, suggesting metabolic defects are paramount. Myocardial metabolomics in human HFpEF has identified reduced fatty acid and branched chain amino acid catabolism, but the status of glycolysis is unknown.

Dysregulated anti-oxidant signalling and compromised mitochondrial integrity negatively influence regulatory T cell function and viability in liver disease.

Background: Dysregulated inflammatory responses and oxidative stress are key pathogenic drivers of chronic inflammatory diseases such as liver cirrhosis (LC). Regulatory T cells (Tregs) are essential to prevent excessive immune activation and maintain tissue homeostasis. While inflammatory cues are well known to modulate the function and stability of Tregs, the extent to which Tregs are influenced by oxidative stress has not been fully explored.

Metabolism in type 2 immune responses.

The immune response is tailored to the environment in which it takes place. Immune cells sense and adapt to changes in their surroundings, and it is now appreciated that in addition to cytokines made by stromal and epithelial cells, metabolic cues provide key adaptation signals. Changes in immune cell activation states are linked to changes in cellular metabolism that support function.

Immunometabolism at the crossroads of obesity and cancer-a Keystone Symposia report.

Immunometabolism considers the relationship between metabolism and immunity. Typically, researchers focus on either the metabolic pathways within immune cells that affect their function or the impact of immune cells on systemic metabolism. A more holistic approach that considers both these viewpoints is needed.

Pyrimidine de novo synthesis inhibition selectively blocks effector but not memory T cell development.

Blocking pyrimidine de novo synthesis by inhibiting dihydroorotate dehydrogenase is used to treat autoimmunity and prevent expansion of rapidly dividing cell populations including activated T cells. Here we show memory T cell precursors are resistant to pyrimidine starvation. Although the treatment effectively blocked effector T cells, the number, function and transcriptional profile of memory T cells and their precursors were unaffected.

Targeting cancer glycosylation repolarizes tumor-associated macrophages allowing effective immune checkpoint blockade.

Immune checkpoint blockade (ICB) has substantially improved the prognosis of patients with cancer, but the majority experiences limited benefit, supporting the need for new therapeutic approaches. Up-regulation of sialic acid-containing glycans, termed hypersialylation, is a common feature of cancer-associated glycosylation, driving disease progression and immune escape through the engagement of Siglec receptors on tumor-infiltrating immune cells. Here, we show that tumor sialylation correlates with distinct immune states and reduced survival in human cancers.