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"Wilkinson, Daniel"
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Immune suppression in gliomas
Introduction
The overall survival in patients with gliomas has not significantly increased in the modern era, despite advances such as immunotherapy. This is in part due to their notorious ability to suppress local and systemic immune responses, severely restricting treatment efficacy.
Methods
We have reviewed the preclinical and clinical evidence for immunosuppression seen throughout the disease process in gliomas. This review aims to discuss the various ways that brain tumors, and gliomas in particular, co-opt the body’s immune system to evade detection and ensure tumor survival and proliferation.
Results
A multitude of mechanisms are discussed by which neoplastic cells evade detection and destruction by the immune system. These include tumor-induced T-cell and NK cell dysfunction, regulatory T-cell and myeloid-derived suppressor cell expansion, M2 phenotypic transformation in glioma-associated macrophages/microglia, upregulation of immunosuppressive glioma cell surface factors and cytokines, tumor microenvironment hypoxia, and iatrogenic sequelae of immunosuppressive treatments.
Conclusions
Gliomas create a profoundly immunosuppressive environment, both locally within the tumor and systemically. Future research should aim to address these immunosuppressive mechanisms in the effort to generate treatment options with meaningful survival benefits for this patient population.
Journal Article
Low‐Carbohydrate Diet Exacerbates Denervation‐Induced Atrophy of Rat Skeletal Muscle Under the Condition of Identical Protein Intake
Background While decreased protein intake is associated with muscle mass loss, it is unclear whether a decrease in carbohydrate intake adversely affects muscle atrophy independently of protein intake. Herein, we examined whether a low‐carbohydrate (low‐CHO) diet exacerbates denervation‐induced muscle atrophy under conditions of identical protein intake. Methods On day one of the experiment, male Wistar rats underwent unilateral denervation. The contralateral leg was used as the control. After denervation, rats were divided into two dietary groups: high‐carbohydrate (high‐CHO) and low‐CHO. Each group was fed a high‐CHO (70% carbohydrate) or low‐CHO (20% carbohydrate) diet over 7 days. Total protein and energy intakes in both groups were matched by pair feeding. Rats were provided with deuterium oxide (D2O) tracer over the last 3 days of dietary intervention to quantify myofibrillar (muscle) protein synthesis (MPS). Results Denervation reduced wet weight of the gastrocnemius muscle compared to the contralateral control (p < 0.05). Reductions in gastrocnemius muscle weight were greater in the low‐CHO group (−34%) than the high‐CHO group (−28%) (p < 0.05). Although denervation decreased MPS compared to the contralateral control (p < 0.05), no dietary effect on MPS was observed. Denervation resulted in increased mRNA and protein expression of Atrogin‐1, a ubiquitin E3 ligase, compared to that in the contralateral control (p < 0.05). Increases in Atrogin‐1 gene and protein expression due to denervation were greater in the low‐CHO group than in the high‐CHO group (p < 0.05). Conclusions We conclude that a low‐CHO diet may exacerbate denervation‐induced atrophy in fast‐twitch‐dominant muscles compared to a high‐CHO diet, even when the same protein intake is maintained. Although blunted MPS contributed to muscle atrophy due to denervation, exacerbation of muscle atrophy by the low‐CHO diet was not accompanied by explanatory changes in MPS. The effect of the low‐CHO diet might be related to promotion of muscle‐specific ubiquitin E3 ligase gene expression.
Journal Article
Mechanistic Links Underlying the Impact of C-Reactive Protein on Muscle Mass in Elderly
Background/Aims: Mechanisms underlying the relationship between systemic inflammation and age-related decline in muscle mass are poorly defined. The purpose of this work was to investigate the relationship between the systemic inflammatory marker CRP and muscle mass in elderly and to identify mechanisms by which CRP mediates its effects on skeletal muscle, in-vitro. Methods: Muscle mass and serum CRP level were determined in a cohort of 118 older women (67±1.7 years). Human muscle cells were differentiated into myotubes and were exposed to CRP. The size of myotubes was determined after immunofluorescent staining using troponin. Muscle protein synthesis was assessed using stable isotope tracers and key signalling pathways controlling protein synthesis were determined using western-blotting. Results: We observed an inverse relationship between circulating CRP level and muscle mass (β= -0.646 (95% CI: -0.888, -0.405) p<0.05) and demonstrated a reduction (p < 0.05) in the size of human myotubes exposed to CRP for 72 h. We next showed that this morphological change was accompanied by a CRP-mediated reduction (p < 0.05) in muscle protein fractional synthetic rate of human myotubes exposed to CRP for 24 h. We also identified a CRP-mediated increased phosphorylation (p<0.05) of regulators of cellular energy stress including AMPK and downstream targets, raptor and ACC-β, together with decreased phosphorylation of Akt and rpS6, which are important factors controlling protein synthesis. Conclusion: This work established for the first time mechanistic links by which chronic elevation of CRP can contribute to age-related decline in muscle function.
Journal Article
Metabolomics as an Important Tool for Determining the Mechanisms of Human Skeletal Muscle Deconditioning
Muscle deconditioning impairs both locomotor function and metabolic health, and is associated with reduced quality life and increased mortality rates. Despite an appreciation of the existence of phenomena such as muscle anabolic resistance, mitophagy, and insulin resistance with age and disease in humans, little is known about the mechanisms responsible for these negative traits. With the complexities surrounding these unknowns and the lack of progress to date in development of effective interventions, there is a need for alternative approaches. Metabolomics is the study of the full array of metabolites within cells or tissues, which collectively constitute the metabolome. As metabolomics allows for the assessment of the cellular metabolic state in response to physiological stimuli, any chronic change in the metabolome is likely to reflect adaptation in the physiological phenotype of an organism. This, therefore, provides a holistic and unbiased approach that could be applied to potentially uncover important novel facets in the pathophysiology of muscle decline in ageing and disease, as well as identifying prognostic markers of those at risk of decline. This review will aim to highlight the current knowledge and potential impact of metabolomics in the study of muscle mass loss and deconditioning in humans and will highlight key areas for future research.
Journal Article
CD8(+) T cells maintain killing of MHC-I-negative tumor cells through the NKG2D-NKG2DL axis
The accepted paradigm for both cellular and anti-tumor immunity relies upon tumor cell killing by CD8 + T cells recognizing cognate antigens presented in the context of target cell major histocompatibility complex (MHC) class I (MHC-I) molecules. Likewise, a classically described mechanism of tumor immune escape is tumor MHC-I downregulation. Here, we report that CD8 + T cells maintain the capacity to kill tumor cells that are entirely devoid of MHC-I expression. This capacity proves to be dependent instead on interactions between T cell natural killer group 2D (NKG2D) and tumor NKG2D ligands (NKG2DLs), the latter of which are highly expressed on MHC-loss variants. Necessarily, tumor cell killing in these instances is antigen independent, although prior T cell antigen-specific activation is required and can be furnished by myeloid cells or even neighboring MHC-replete tumor cells. In this manner, adaptive priming can beget innate killing. These mechanisms are active in vivo in mice as well as in vitro in human tumor systems and are obviated by NKG2D knockout or blockade. These studies challenge the long-advanced notion that downregulation of MHC-I is a viable means of tumor immune escape and instead identify the NKG2D–NKG2DL axis as a therapeutic target for enhancing T cell-dependent anti-tumor immunity against MHC-loss variants.
Journal Article
IL7 and IL7 Flt3L co-expressing CAR T cells improve therapeutic efficacy in mouse EGFRvIII heterogeneous glioblastoma
Chimeric antigen receptor (CAR) T cell therapy in glioblastoma faces many challenges including insufficient CAR T cell abundance and antigen-negative tumor cells evading targeting. Unfortunately, preclinical studies evaluating CAR T cells in glioblastoma focus on tumor models that express a single antigen, use immunocompromised animals, and/or pre-treat with lymphodepleting agents. While lymphodepletion enhances CAR T cell efficacy, it diminishes the endogenous immune system that has the potential for tumor eradication. Here, we engineered CAR T cells to express IL7 and/or Flt3L in 50% EGFRvIII-positive and -negative orthotopic tumors pre-conditioned with non-lymphodepleting irradiation. IL7 and IL7 Flt3L CAR T cells increased intratumoral CAR T cell abundance seven days after treatment. IL7 co-expression with Flt3L modestly increased conventional dendritic cells as well as the CD103+XCR1+ population known to have migratory and antigen cross-presenting capabilities. Treatment with IL7 or IL7 Flt3L CAR T cells improved overall survival to 67% and 50%, respectively, compared to 9% survival with conventional or Flt3L CAR T cells. We concluded that CAR T cells modified to express IL7 enhanced CAR T cell abundance and improved overall survival in EGFRvIII heterogeneous tumors pre-conditioned with non-lymphodepleting irradiation. Potentially IL7 or IL7 Flt3L CAR T cells can provide new opportunities to combine CAR T cells with other immunotherapies for the treatment of glioblastoma.
Journal Article
Rapamycin Exerts Its Geroprotective Effects in the Ageing Human Immune System by Enhancing Resilience Against DNA Damage
mTOR inhibitors such as rapamycin are among the most robust life‐extending interventions known, yet the mechanisms underlying their geroprotective effects in humans remain incompletely understood. At non‐immunosuppressive doses, these drugs are senomorphic, that is, they mitigate cellular senescence, but whether they protect genome stability itself has been unclear. Given that DNA damage is a major driver of immune ageing, and immune decline accelerates whole‐organism ageing, we tested whether mTOR inhibition enhances genome stability. In human T cells exposed to acute genotoxic stress, we found that rapamycin and other mTOR inhibitors suppressed senescence not by slowing protein synthesis, halting cell division, or stimulating autophagy, but by directly reducing DNA lesional burden and improving cell survival. Ex vivo analysis of aged immune cells from healthy donors revealed a stark enrichment of markers for DNA damage, senescence, and mTORC hyperactivation, suggesting that human immune ageing may be amenable to intervention by low‐dose mTOR inhibition. To test this in vivo, we conducted a placebo‐controlled experimental medicine study in older adults administered with low‐dose rapamycin. p21, a marker of DNA damage‐induced senescence, was significantly reduced in immune cells from the rapamycin compared to placebo group. These findings reveal a previously unrecognised role for mTOR inhibition: direct genoprotection. This mechanism may help explain rapamycin's exceptional geroprotective profile and opens new avenues for its use in contexts where genome instability drives pathology, ranging from healthy ageing, clinical radiation exposure and even the hazards of cosmic radiation in space travel. Using in vitro DNA damage assays in human T cells, ex vivo profiling of aged immune subsets and a small placebo‐controlled in vivo study, authors show that low‐dose rapamycin, a potent life‐extending mTOR inhibitor, enhances resilience against DNA damage in the human immune system.
Journal Article
Declines in muscle protein synthesis account for short‐term muscle disuse atrophy in humans in the absence of increased muscle protein breakdown
Background We determined the short‐term (i.e. 4 days) impacts of disuse atrophy in relation to muscle protein turnover [acute fasted‐fed muscle protein synthesis (MPS)/muscle protein breakdown (MPB) and integrated MPS/estimated MPB]. Methods Healthy men (N = 9, 22 ± 2 years, body mass index 24 ± 3 kg m−2) underwent 4 day unilateral leg immobilization. Vastus lateralis (VL) muscle thickness (MT) and extensor strength and thigh lean mass (TLM) were measured. Bilateral VL muscle biopsies were collected on Day 4 at t = −120, 0, 90, and 180 min to determine integrated MPS, estimated MPB, acute fasted‐fed MPS (l‐[ring‐13C6]‐phe), and acute fasted tracer decay rate representative of MPB (l‐[15N]‐phe and l‐[2H8]‐phe). Protein turnover cell signalling was measured by immunoblotting. Results Immobilization decreased TLM [pre: 7477 ± 1196 g, post: 7352 ± 1209 g (P < 0.01)], MT [pre: 2.67 ± 0.50 cm, post: 2.55 ± 0.51 cm (P < 0.05)], and strength [pre: 260 ± 43 N m, post: 229 ± 37 N m (P < 0.05)] with no change in control legs. Integrated MPS decreased in immob vs. control legs [control: 1.55 ± 0.21% day−1, immob: 1.29 ± 0.17% day−1 (P < 0.01)], while tracer decay rate (i.e. MPB) (control: 0.02 ± 0.006, immob: 0.015 ± 0.015) and fractional breakdown rate (FBR) remained unchanged [control: 1.44 ± 0.51% day−1, immob: 1.73 ± 0.35% day−1 (P = 0.21)]. Changes in MT correlated with those in MPS but not FBR. MPS increased in the control leg following feeding [fasted: 0.043 ± 0.012% h−1, fed: 0.065 ± 0.017% h−1 (P < 0.05)] but not in immob [fasted: 0.034 ± 0.014% h−1, fed: 0.049 ± 0.023% h−1 (P = 0.09)]. There were no changes in markers of MPB with immob (P > 0.05). Conclusions Human skeletal muscle disuse atrophy is driven by declines in MPS, not increases in MPB. Pro‐anabolic therapies to mitigate disuse atrophy would likely be more effective than therapies aimed at attenuating protein degradation.
Journal Article