Abstract
Remarkable progress in cancer immunotherapy has revealed the power of harnessing immunity to combat cancer. Anti-tumor T cells suppress tumor development by secreting cytotoxic cytokines and ...activating other immune cells. However, the tumoricidal function of tumor-infiltrating T cells is often suppressed and inefficient to combat tumors. Thus one of the key questions in the field of cancer immunology is to address what causes the immunosuppressive nature of the tumor microenvironment. Using a melanoma mouse model, we found that 1) fatty acids accumulated in the tumor microenvironment, 2) unsaturated fatty acids suppressed T cell effector function through CD36/PPAR pathway and 3) blocking FAs transportation into T cells enhanced T cell cytotoxicity and delayed tumor growth. This study has identified unsaturated fatty acid species as immunosuppressive factors in tumor, which may lead to the development of novel forms of therapy that stimulates anti-tumor immunity by manipulating fatty acid transportation and metabolism.
Abstract
Glycerol channel aquaporin 9 (AQP9) has been reported to be highly expressed in memory CD8 T cells post infection, but its function in memory CD8 T cells formation remains unknown. In this ...study, we report that AQP9 is vitally required for survival and differentiation of memory T cells after viral infection. AQP9 imports glycerol into cells for fatty acid esterification and triglyceride storage. Loss of AQP9 substantially impaired lipid storage and caused antiviral CD8 T cells sensitive to apoptosis. Interestingly, this defect could be rescued by ectopic expression of glycerol channels or triglyceride synthases. Furthermore, IL-7 induces AQP9 expression dependent on Foxo1 pathway. This study revealed an unexpected role of glycerol in CD8 T cell fate decision by regulating energy storage.
Activated T cells engage aerobic glycolysis and anabolic metabolism for growth, proliferation, and effector functions. We propose that a glucose-poor tumor microenvironment limits aerobic glycolysis ...in tumor-infiltrating T cells, which suppresses tumoricidal effector functions. We discovered a new role for the glycolytic metabolite phosphoenolpyruvate (PEP) in sustaining T cell receptor-mediated Ca2+-NFAT signaling and effector functions by repressing sarco/ER Ca2+-ATPase (SERCA) activity. Tumor-specific CD4 and CD8 T cells could be metabolically reprogrammed by increasing PEP production through overexpression of phosphoenolpyruvate carboxykinase 1 (PCK1), which bolstered effector functions. Moreover, PCK1-overexpressing T cells restricted tumor growth and prolonged the survival of melanoma-bearing mice. This study uncovers new metabolic checkpoints for T cell activity and demonstrates that metabolic reprogramming of tumor-reactive T cells can enhance anti-tumor T cell responses, illuminating new forms of immunotherapy.
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•Glucose deprivation suppresses anti-tumor T cell effector functions•Glycolytic metabolite PEP sustains Ca2+ and NFAT signaling by blocking SERCA•Ca2+ signaling is an integrator of glycolytic activity and TCR signaling•T cell metabolic reprogramming enhances anti-tumor effector functions
High rates of tumor cell glycolysis suppress intratumoral T cell function by depriving T cells of glucose and the downstream metabolite phosphoenolpyruvate (PEP), which is necessary for maximal Ca2+ -NFAT signaling in T cells. Metabolic rewiring of T cells to generate PEP in glucose-poor conditions improves their anti-tumor responses.
Memory T cells are critical for long-term immunity against reinfection and require interleukin-7 (IL-7), but the mechanisms by which IL-7 controls memory T cell survival, particularly metabolic ...fitness, remain elusive. We discover that IL-7 induces expression of the glycerol channel aquaporin 9 (AQP9) in virus-specific memory CD8+ T cells, but not naive cells, and that AQP9 is vitally required for their long-term survival. AQP9 deficiency impairs glycerol import into memory CD8+ T cells for fatty acid esterification and triglyceride (TAG) synthesis and storage. These defects can be rescued by ectopic expression of TAG synthases, which restores lipid stores and memory T cell survival. Finally, we find that TAG synthesis is a central component of IL-7-mediated survival of human and mouse memory CD8+T cells. This study uncovers the metabolic mechanisms by which IL-7 tailors the metabolism of memory T cells to promote their longevity and fast response to rechallenge.
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•IL-7 induces glycerol channel AQP9 expression in CD8+ T cells•AQP9 is required for memory CD8+ T cell survival and self-renewal•AQP9 imports glycerol, promotes TAG synthesis, and sustains ATP levels in T cells•IL-7 enhances TAG synthesis to promote memory CD8+ T cell survival
Interleukin-7 induces expression of the glycerol channel aquaporin 9, allowing memory CD8+ T cells to import glycerol, use it for triglyceride synthesis and storage, and sustain ATP levels required for long-term metabolic fitness and fast responses to reinfection.
Protein kinase B (also known as AKT) and the mechanistic target of rapamycin (mTOR) are central regulators of T cell differentiation, proliferation, metabolism, and survival. Here, we show that ...during chronic murine lymphocytic choriomeningitis virus infection, activation of AKT and mTOR are impaired in antiviral cytotoxic T lymphocytes (CTLs), resulting in enhanced activity of the transcription factor FoxO1. Blockade of inhibitory receptor programmed cell death protein 1 (PD-1) in vivo increased mTOR activity in virus-specific CTLs, and its therapeutic effects were abrogated by the mTOR inhibitor rapamycin. FoxO1 functioned as a transcriptional activator of PD-1 that promoted the differentiation of terminally exhausted CTLs. Importantly, FoxO1-null CTLs failed to persist and control chronic viral infection. Collectively, this study shows that CTLs adapt to persistent infection through a positive feedback pathway (PD-1→FoxO1→PD-1) that functions to both desensitize virus-specific CTLs to antigen and support their survival during chronic viral infection.
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•TCR activation of AKT and mTOR is impaired in exhausted CTLs•Therapeutic blockade of PD-1 signaling is mTOR dependent•FoxO1 is necessary to sustain CTL responses and control chronic viral infection•FoxO1 regulates the expression and differentiation of PD-1hi exhausted CTLs
Chronic infection can lead to a state of CD8+ T cell dysfunction referred to as exhaustion. Kaech and colleagues show that the transcription factor FoxO1 promotes the differentiation and maintenance of exhausted CD8+ T cells to control chronic viral infection.
Lithium-sulfur (Li-S) batteries hold great promise for next-generation electronics owing to their high theoretical energy density, low cost, and eco-friendliness. Nevertheless, the practical ...implementation of Li-S batteries is hindered by the shuttle effect and sluggish reaction kinetics of polysulfides. Herein, the spray drying and chemical etching strategies are implemented to fabricate hierarchically porous MXene microspheres as a multifunctional sulfur electrocatalyst. The interconnected skeleton offers uniform sulfur distribution and prevents the restacking of MXene sheets, while the abundant edges endow the nanosheet-like Ti
C
with rich active sites and regulated a d-band center of Ti atoms, leading to strong lithium polysulfide (LiPS) adsorption. The unsaturated Ti on edge sites can further act as multifunctional sites for chemically anchoring LiPS and lowering Li-ion migration barriers, accelerating LiPS conversion. Owing to these structural advantages, excellent cycling and rate performances of the sulfur cathode can be obtained, even under a raised sulfur loading and lean electrolyte content.
Protective effect of Tagetes erecta flowers essential oils was investigated on oxidative stress, immune response, inflammation, and apoptosis against N-methyl-NEnitro-N-nitroguanidine (MNNG) induced ...gastric cancer in rats. Essential oil were extracted from Tagetes erecta flowers and analyzed using gas chromatography-mass spectrometry (GC-MS). For observing a protective effect against MNNG induced gastric cancer, we divided rats into 4 groups (group A to D) having 10 rats in each group. Performed various experiments and measured a different parameters to investigate antioxidant activity, immune response, anti-inflammatory and anti-apoptotic activity. The levels of malondialdehyde were markedly increased in the presence of N-methyl-NEnitro-N-nitroguanidine, whereas, the antioxidant activities of superoxide dismutase, and catalase were lowered in the treated rats in contrast with the control. Intervention with TEEO to gastric cancer-induced rats upregulated the redox status and the activity of the immune system to decrease cancer risk. The proinflammatory cytokines (IL-6 and TNF-alpha) secretions that were induced by MNNG were markedly inhibited by TEEO. Administration of TEEO also significantly reduced terminal deoxynucleotidyl transferase dUTP nick end labeling positive gastric cancer cells, expression of mRNA of caspase-3, and Bax. Whereas, the expression of Bcl-2 was increased. Additionally, downregulation of nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) and IkappaBalpha degradation and the nuclear factor-kappaB (NF-kappaB) p65 expression in tissues of the stomach of MNNG-induced-rats were markedly elevated due to TEEO. This suggested possession of TEEO with a protective shield against MNNG induced gastric cancer by the exertion of antioxidative stress, anti-apoptotic response, the anti-inflammatory response through Nrf2/HO-1, and NF-kappaB signaling pathways.
To maintain immune tolerance, effector T‐cell (Teff) responses must be checked by the regulatory T cells (Tregs) in time. It remains incompletely understood how Tregs sense real‐time Teff activation. ...Here, we report that the AP‐1 transcription factor JunB, which is induced in Teffs upon T‐cell receptor (TCR) activation, is also increased in Tregs by TCR stimuli. Treg‐specific deletion of Junb impairs Treg identity, causes uncontrolled inflammatory cytokine production by Teffs and leads to the T‐box transcription factor T‐bet‐dependent spontaneous inflammation. Furthermore, JunB deficiency in Tregs unleashes antitumor Teff responses in a mouse model of melanoma. We conclude that JunB alarms Tregs of the emerging Teff activation and synchronizes immune regulation with the immune reaction in autoimmunity and cancer.
Ras-related Protein Rap1b, a GTP-binding protein belonging to the proximal RAS, which affects tumor progression through regulating tumor cell proliferation, invasion and participates in the functions ...of various immune cells. However, the potential roles and mechanisms of Rap1b in tumor progression and immunology remains unclear. In this study, we systematically analyzed the pan-cancer expression and prognostic correlation of Rap1b based on GTEX, CCLE, Oncomine, PrognoScan, Kaplan-Meier plotters and TCGA databases. The potential correlations of Rap1b with immune infiltration were revealed via TIMER and TCGA database. SangerBox database was used to analyzed the correlations between Rap1b expression and immune checkpoint (ICP), tumor mutational burden (TMB), microsatellite instability (MSI), mismatch repairs (MMRs) and DNA methylation. The results indicated that the expression level of Rap1b varies in different tumors. Meanwhile, the expression level of Rap1b strongly correlated with prognosis in patients with tumors, higher expression of Rap1b usually was linked to poor prognosis in different datasets. Rap1b was correlated closely with tumor immunity and interacted with various immune cells in different types of cancers. In addition, there were significant positive correlations between Rap1b expression and ICP, TMB, MSI, MMRs and DNA methylation. In conclusion, the results of pan-cancer analysis showed that the abnormal Rap1b expression was related to poor prognosis and tumor immune infiltration in different cancers. Furthermore, Rap1b gene may be used as a potential biomarker of clinical tumor prognosis.
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