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.
In systemic lupus erythematosus (SLE), cardiac manifestations, e.g. coronary artery disease (CAD) and myocarditis are leading causes of morbidity and mortality. The prevalence of subclinical heart ...disease in SLE is unknown. We studied whether a comprehensive cardiovascular magnetic resonance (CMR) protocol may be useful for early diagnosis of heart disease in SLE patients without known CAD.
In this prospective, observational, cross-sectional study CMR including cine, late gadolinium enhancement (LGE) and stress perfusion sequences, ECG, and blood sampling were performed in 30 consecutive SLE patients without known CAD. All patients fulfilled at least 4/11 American College of Rheumatology (ACR) Criteria for the classification of SLE.
30 patients (83% female) were enrolled, mean age was 45±14 years and mean SLE disease duration was 10±8 years. 80% had low to moderate disease activity. All had a low SLE damage index. CMR was abnormal in 13/30 (43%), showing LGE in 9/13, stress perfusion deficits in 5/13 and pericardial effusion (PE) in 7/13. Patients with non-ischemic LGE had more often microalbuminuria while patients with stress perfusion deficits a history of hypertension, renal disorder as ACR criterion, repolarisation abnormalities on ECG and larger LV enddiastolic volume index. There was no correlation between clinical symptoms and CMR results.
Our study shows that cardiac involvement as observed by CMR is frequent in SLE and not necessarily associated with typical symptoms. CMR may thus help to detect subclinical cardiac involvement, which could lead to earlier treatment. Additionally we identify possible risk factors associated with cardiac involvement.
Mitochondria are important regulators of macrophage polarisation. Here, we show that arginase-2 (Arg2) is a microRNA-155 (miR-155) and interleukin-10 (IL-10) regulated protein localized at the ...mitochondria in inflammatory macrophages, and is critical for IL-10-induced modulation of mitochondrial dynamics and oxidative respiration. Mechanistically, the catalytic activity and presence of Arg2 at the mitochondria is crucial for oxidative phosphorylation. We further show that Arg2 mediates this process by increasing the activity of complex II (succinate dehydrogenase). Moreover, Arg2 is essential for IL-10-mediated downregulation of the inflammatory mediators succinate, hypoxia inducible factor 1α (HIF-1α) and IL-1β in vitro. Accordingly, HIF-1α and IL-1β are highly expressed in an LPS-induced in vivo model of acute inflammation using Arg2
mice. These findings shed light on a new arm of IL-10-mediated metabolic regulation, working to resolve the inflammatory status of the cell.
Tumor-specific T cells are frequently exhausted by chronic antigenic stimulation. We here report on a human antigen-specific ex vivo model to explore new therapeutic options for T cell ...immunotherapies. T cells generated with this model resemble tumor-infiltrating exhausted T cells on a phenotypic and transcriptional level. Using a targeted pooled CRISPR-Cas9 screen and individual gene knockout validation experiments, we uncover sorting nexin-9 (SNX9) as a mediator of T cell exhaustion. Upon TCR/CD28 stimulation, deletion of SNX9 in CD8 T cells decreases PLCγ1, Ca
, and NFATc2-mediated T cell signaling and reduces expression of NR4A1/3 and TOX. SNX9 knockout enhances memory differentiation and IFNγ secretion of adoptively transferred T cells and results in improved anti-tumor efficacy of human chimeric antigen receptor T cells in vivo. Our findings highlight that targeting SNX9 is a strategy to prevent T cell exhaustion and enhance anti-tumor immunity.
Complement is well appreciated as a critical arm of innate immunity. It is required for the removal of invading pathogens and works by directly destroying them through the activation of innate and ...adaptive immune cells. However, complement activation and function is not confined to the extracellular space but also occurs within cells. Recent work indicates that complement activation regulates key metabolic pathways and thus can impact fundamental cellular processes, such as survival, proliferation, and autophagy. Newly identified functions of complement include a key role in shaping metabolic reprogramming, which underlies T cell effector differentiation, and a role as a nexus for interactions with other effector systems, in particular the inflammasome and Notch transcription-factor networks. This review focuses on the contributions of complement to basic processes of the cell, in particular the integration of complement with cellular metabolism and the potential implications in infection and other disease settings.
Serum-circulating complement is critical for protection against invading pathogens. However, it is becoming increasingly clear that the complement system serves additional “non-classical” roles. Hess and Kemper discuss newly described intracellular and autocrine functions of complement in the regulation of metabolism and basic cellular processes.
The innate immune system safeguards the organism from both pathogenic and environmental stressors. Also, physiologic levels of nutrients affect organismal and intra-cellular metabolism and challenge ...the immune system. In the long term, over-nutrition leads to low-grade systemic inflammation. Here, we investigate tissue-resident components of the innate immune system (macrophages) and their response to short- and long-term nutritional challenges. We analyze the transcriptomes of six tissue-resident macrophage populations upon acute feeding and identify adipose tissue macrophages and the IL-1 pathway as early sensors of metabolic changes. Furthermore, by comparing functional responses between macrophage subtypes, we propose a regulatory, anti-inflammatory role of heat shock proteins of the HSP70 family in response to long- and short-term metabolic challenges. Our data provide a resource for assessing the impact of nutrition and over-nutrition on the spectrum of macrophages across tissues with a potential for identification of systemic responses.
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•Transcriptome resource for scarce macrophage populations upon a single feeding•Feeding upregulates the IL-1 pathway selectively in adipose tissue macrophages•Heat shock proteins regulate macrophage responses to nutritional challenge
Brykczynska et al. investigate the response of tissue-resident macrophages to short- and long-term nutritional challenges. They identify adipose tissue macrophages and the IL-1 pathway as early sensors of metabolic changes and propose a regulatory role for heat shock proteins in response to acute and chronic metabolic perturbances.
Tumor cells undergo uncontrolled proliferation driven by enhanced anabolic metabolism including glycolysis and glutaminolysis. Targeting these pathways to inhibit cancer growth is a strategy for ...cancer treatment. Critically, however, tumor-responsive T cells share metabolic features with cancer cells, making them susceptible to these treatments as well. Here, we assess the impact on anti-tumor T cell immunity and T cell exhaustion by genetic ablation of lactate dehydrogenase A (LDHA) and glutaminase1 (GLS1), key enzymes in aerobic glycolysis and glutaminolysis. Loss of LDHA severely impairs expansion of T cells in response to tumors and chronic infection. In contrast, T cells lacking GLS1 can compensate for impaired glutaminolysis by engaging alternative pathways, including upregulation of asparagine synthetase, and thus efficiently respond to tumor challenge and chronic infection as well as immune checkpoint blockade. Targeting GLS1-dependent glutaminolysis, but not aerobic glycolysis, may therefore be a successful strategy in cancer treatment, particularly in combination with immunotherapy.
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•LDHA deletion impairs CD8 T cell proliferation and differentiation but not effector function•T cells lacking GLS1 show unimpaired differentiation and effector function•Glutamine is required for demethylation and transcription of Ifng in memory T cells
Interfering with cell metabolism is a strategy to inhibit tumor growth, but it may also impact T cells that are key for anti-tumor immunity. Gubser et al. define GLS1 as a target that does not affect T cell responses against cancer. In contrast, LDHA is essential for the anti-tumor activity of T cells.
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.
Gas attenuators are important devices providing accurate variation of photon intensity for soft X‐ray beamlines. In the SwissFEL ATHOS beamline front‐end the space is very limited and an innovative ...approach has been taken to provide attenuation of three orders of magnitude up to an energy of 1200 eV. Additive manufacturing of a differential pumping system vacuum manifold allowed a triple pumping stage to be realized in a space of less than half a meter. Measurements have shown that the response of the device is as expected from theoretical calculations.
A compact gas attenuator for the SwissFEL ATHOS beamline with a custom manifold realized using additive manufacturing is described. First results show that the response is as expected from theoretical calculations.
Despite the tremendous success of adoptive T-cell therapies (ACT) in fighting certain hematologic malignancies, not all patients respond, a proportion experience relapse, and effective ACT of most ...solid tumors remains elusive. In order to improve responses to ACT suppressive barriers in the solid tumor microenvironment (TME) including insufficient nutrient availability must be overcome. Here we explored how enforced expression of the high-affinity glucose transporter GLUT3 impacted tumor-directed T cells. Overexpression of GLUT3 in primary murine CD8
+
T cells enhanced glucose uptake and increased glycogen and fatty acid storage, and was associated with increased mitochondrial fitness, reduced ROS levels, higher abundance of the anti-apoptotic protein Mcl-1, and better resistance to stress. Importantly, GLUT3-OT1 T cells conferred superior control of B16-OVA melanoma tumors and, in this same model, significantly improved survival. Moreover, a proportion of treated mice were cured and protected from re-challenge, indicative of long-term T cell persistence and memory formation. Enforcing expression of GLUT3 is thus a promising strategy to improve metabolic fitness and sustaining CD8
+
T cell effector function in the context of ACT.
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