Immune suppression in gliomas Grabowski, Matthew M.; Sankey, Eric W.; Ryan, Katherine J. ...
Journal of neuro-oncology,
01/2021, Letnik:
151, Številka:
1
Journal Article
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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.
The ever increasing burden of an aging population and pandemic of metabolic syndrome worldwide demands further understanding of the modifiable risk factors in reducing disability and morbidity ...associated with these conditions. Disuse skeletal muscle atrophy (sometimes referred to as "simple" atrophy) and insulin resistance are "non-pathological" events resulting from sedentary behavior and periods of enforced immobilization e.g., due to fractures or elective orthopedic surgery. Yet, the processes and drivers regulating disuse atrophy and insulin resistance and the associated molecular events remain unclear-especially in humans. The aim of this review is to present current knowledge of relationships between muscle protein turnover, insulin resistance and muscle atrophy during disuse, principally in humans. Immobilization lowers fasted state muscle protein synthesis (MPS) and induces fed-state "anabolic resistance." While a lack of dynamic measurements of muscle protein breakdown (MPB) precludes defining a definitive role for MPB in disuse atrophy, some proteolytic "marker" studies (e.g., MPB genes) suggest a potential early elevation. Immobilization also induces muscle insulin resistance (IR). Moreover, the trajectory of muscle atrophy appears to be accelerated in persistent IR states (e.g., Type II diabetes), suggesting IR may contribute to muscle disuse atrophy under these conditions. Nonetheless, the role of differences in insulin sensitivity across distinct muscle groups and its effects on rates of atrophy remains unclear. Multifaceted time-course studies into the collective role of insulin resistance and muscle protein turnover in the setting of disuse muscle atrophy, in humans, are needed to facilitate the development of appropriate countermeasures and efficacious rehabilitation protocols.
In chronic infections and in cancer, persistent antigen stimulation under suboptimal conditions can lead to the induction of T-cell exhaustion. Exhausted T cells are characterized by an increased ...expression of inhibitory markers and a progressive and hierarchical loss of function. Although cancer-induced exhaustion in CD8 T cells has been well-characterized and identified as a therapeutic target (i.e., via checkpoint inhibition), in-depth analyses of exhaustion in other immune cell types, including CD4 T cells, is wanting. While perhaps attributable to the contextual discovery of exhaustion amidst chronic viral infection, the lack of thorough inquiry into CD4 T-cell exhaustion is particularly surprising given their important role in orchestrating immune responses through T-helper and direct cytotoxic functions. Current work suggests that CD4 T-cell exhaustion may indeed be prevalent, and as CD4 T cells have been implicated in various disease pathologies, such exhaustion is likely to be clinically relevant. Defining phenotypic exhaustion in the various CD4 T-cell subsets and how it influences immune responses and disease severity will be crucial to understanding collective immune dysfunction in a variety of pathologies. In this review, we will discuss mechanistic and clinical evidence for CD4 T-cell exhaustion in cancer. Further insight into the derivation and manifestation of exhaustive processes in CD4 T cells could reveal novel therapeutic targets to abrogate CD4 T-cell exhaustion in cancer and induce a robust antitumor immune response.
ABSTRACT
Resistance exercise training (RET) is widely used to increase muscle mass in athletes and also aged/cachectic populations. However, the time course and metabolic and molecular control of ...hypertrophy remain poorly defined. Using newly developed deuterium oxide (D2O)‐tracer techniques, we investigated the relationship between long‐term muscle protein synthesis (MPS) and hypertrophic responses to RET. A total of 10 men (23 ± 1 yr) undertook 6 wk of unilateral (1‐legged) RET 6 × 8 repetitions, 75% 1 repetition maximum (1‐RM) 3/wk, rendering 1 leg untrained (UT) and the contralateral, trained (T). After baseline bilateral vastus lateralis (VL) muscle biopsies, subjects consumed 150 ml D2O (70 atom percentage; thereafter 50 ml/wk) with regular body water monitoring in saliva via high‐temperature conversion elemental analyzer:isotope ratio mass spectrometer. Further bilateral VL muscle biopsies were taken at 3 and 6 wk to temporally quantify MPS via gas chromatography:pyrolysis:isotope ratio mass spectrometer. Expectedly, only the T leg exhibited marked increases in function i.e., 1‐RM/maximal voluntary contraction (60°) and VL thickness (peaking at 3 wk). Critically, whereas MPS remained unchanged in the UT leg (e.g., ∼1.35 ± 0.08%/d), the T leg exhibited increased MPS at 0‐3 wk (1.6 ± 0.01%/d), but not at 3‐6 wk (1.29 ± 0.11%/d); this was reflected by dampened acute mechanistic target of rapamycin complex 1 signaling responses to RET, beyond 3 wk. Therefore, hypertrophic remodeling is most active during the early stages of RET, reflecting longer‐term MPS. Moreover, D2O heralds promise for coupling MPS and muscle mass and providing insight into the control of hypertrophy and efficacy of anabolic interventions.—Brook, M. S., Wilkinson, D. J., Mitchell, W. K., Lund, J. N., Szewczyk, N. J., Greenhaff, P. L., Smith, K., Atherton, P. J. Skeletal muscle hypertrophy adaptations predominate in the early stages of resistance exercise training, matching deuterium oxide‐derived measures of muscle protein synthesis and mechanistic target of rapamycin complex 1 signaling. FASEB J. 29, 4485‐4496 (2015). www.fasebj.org
Key points
Resistance exercise training (RET) is one of the most effective strategies for preventing declines in skeletal muscle mass and strength with age.
Hypertrophic responses to RET with age are ...diminished compared to younger individuals.
In response to 6 weeks RET, we found blunted hypertrophic responses with age are underpinned by chronic deficits in long‐term muscle protein synthesis.
We show this is likely to be the result of multifactorial deficits in anabolic hormones and blunted translational efficiency and capacity.
These results provide great insight into age‐related exercise adaptations and provide a platform on which to devise appropriate nutritional and exercise interventions on a longer term basis.
Ageing is associated with impaired hypertrophic responses to resistance exercise training (RET). Here we investigated the aetiology of ‘anabolic resistance’ in older humans. Twenty healthy male individuals, 10 younger (Y; 23 ± 1 years) and 10 older (O; 69 ± 3 years), performed 6 weeks unilateral RET (6 × 8 repetitions, 75% of one repetition maximum (1‐RM), 3 times per week). After baseline bilateral vastus lateralis (VL) muscle biopsies, subjects consumed 150 ml D2O (70 atom%; thereafter 50 ml week−1), further bilateral VL muscle biopsies were taken at 3 and 6 weeks to quantify muscle protein synthesis (MPS) via gas chromatography–pyrolysis–isotope ratio mass spectrometry. After RET, 1‐RM increased in Y (+35 ± 4%) and O (+25 ± 3%; P < 0.01), while MVC increased in Y (+21 ± 5%; P < 0.01) but not O (+6 ± 3%; not significant (NS)). In comparison to Y, O displayed blunted RET‐induced increases in muscle thickness (at 3 and 6 weeks, respectively, Y: +8 ± 1% and +11 ± 2%, P < 0.01; O: +2.6 ± 1% and +3.5 ± 2%, NS). While ‘basal’ longer term MPS was identical between Y and O (∼1.35 ± 0.1% day−1), MPS increased in response to RET only in Y (3 weeks, Y: 1.61 ± 0.1% day−1; O: 1.49 ± 0.1% day−1). Consistent with this, O exhibited inferior ribosomal biogenesis (RNA:DNA ratio and c‐MYC induction: Y: +4 ± 2 fold change; O: +1.9 ± 1 fold change), translational efficiency (S6K1 phosphorylation, Y: +10 ± 4 fold change; O: +4 ± 2 fold change) and anabolic hormone milieu (testosterone, Y: 367 ± 19; O: 274 ± 19 ng dl−1 (all P < 0.05). Anabolic resistance is thus multifactorial.
Key points
Resistance exercise training (RET) is one of the most effective strategies for preventing declines in skeletal muscle mass and strength with age.
Hypertrophic responses to RET with age are diminished compared to younger individuals.
In response to 6 weeks RET, we found blunted hypertrophic responses with age are underpinned by chronic deficits in long‐term muscle protein synthesis.
We show this is likely to be the result of multifactorial deficits in anabolic hormones and blunted translational efficiency and capacity.
These results provide great insight into age‐related exercise adaptations and provide a platform on which to devise appropriate nutritional and exercise interventions on a longer term basis.
This study examines nominal derivational affixes in a multilingual practice in the Philippines involving Hokkien, Tagalog, and English called Lánnang-uè. A feature of this practice is the systematic ...combination of affixes and roots (henceforth, 'system'). Certain morphological combinations (e.g. Tagalog prefixes + English root) are used frequently and are regarded by Lánnang-uè users as well-formed, while others are not. This paper seeks to examine the spread, stability, and possible patterns of sociolinguistically-conditioned variation involving this system in the Lánnang-uè-speaking community. I conducted an acceptability judgment experiment involving 65 users in Manila and found high rates of spread and stability within my sample. Factors such as age, sex, and attitudes towards mixing selectively conditioned how some speakers adhered to system. For example, older users tended not to follow the affix source language, length, and position condition of the system whereas male users only tended not to follow the first condition. Based on the findings, I argue that the derivational affixation system exhibits conventionalisation, and that it emerged due to identity negotiation practices led by younger and female users. I also argue that conscious positive attitudes towards mixing help shape the stable development of multilingual practices.
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Immunotherapies, such as immune checkpoint inhibition (ICI), have had limited success in treating intracranial malignancies. These failures are due partly to the restrictive ...blood–brain-barrier (BBB), the profound tumor-dependent induction of local and systemic immunosuppression, and immune evasion exhibited by these tumors. Therefore, novel approaches must be explored that aim to overcome these stringent barriers.
LITT is an emerging treatment for brain tumors that utilizes thermal ablation to kill tumor cells. LITT provides an additional therapeutic benefit by synergizing with ICI and systemic chemotherapies to strengthen the anti-tumor immune response. This synergistic relationship involves transient disruption of the BBB and local augmentation of immune function, culminating in increased CNS drug penetrance and improved anti-tumor immunity.
In this review, we will provide an overview of the challenges facing immunotherapy for brain tumors, and discuss how LITT may synergize with the endogenous anti-tumor response to improve the efficacy of ICI.
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.
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.
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.
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.
This work established for the first time mechanistic links by which chronic elevation of CRP can contribute to age-related decline in muscle function.
Muscle atrophy and sarcopenia (the term given to the age-related decline in muscle mass and function), influence an individuals risk of falls, frailty, functional decline, and, ultimately, impaired ...quality of life. Vitamin D deficiency (low serum levels of 25-hydroxyvitamin D (25(OH)D3)) has been reported to impair muscle strength and increase risk of sarcopenia. The mechanisms that underpin the link between low 25(OH)D3 and sarcopenia are yet to be fully understood but several lines of evidence have highlighted the importance of both genomic and non-genomic effects of active vitamin D (1,25-dihydroxyvitamin D (1,25(OH)2D3)) and its nuclear vitamin D receptor (VDR), in skeletal muscle functioning. Studies in vitro have demonstrated a key role for the vitamin D/VDR axis in regulating biological processes central to sarcopenic muscle atrophy, such as proteolysis, mitochondrial function, cellular senescence, and adiposity. The aim of this review is to provide a mechanistic overview of the proposed mechanisms for the vitamin D/VDR axis in sarcopenic muscle atrophy.
•Vitamin D deficiency is prevalent and it impacts musculoskeletal health negatively, therefore warranting future research.•This review synthesises how the vitamin D/VDR axis may impact systems biology within skeletal muscle.•We provide a working model of mechanistic links between the vitamin D/VDR axis and muscle biology.
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