bims-glecem 2022-04-03 papers

bims-glecem

Biomed News

on Glycogen metabolism in exercise, cancer and energy metabolism

Issue of 2022–04–03
eleven papers selected by
Dipsikha Biswas, Københavns Universitet

A century of exercise physiology: key concepts in regulation of glycogen metabolism in skeletal muscle.
Altered electrical properties in skeletal muscle of mice with glycogen storage disease type II.
AAV-Mediated Artificial miRNA Reduces Pathogenic Polyglucosan Bodies and Neuroinflammation in Adult Polyglucosan Body and Lafora Disease Mouse Models.
Human tau accumulation promotes glycogen synthase kinase-3β acetylation and thus upregulates the kinase: A vicious cycle in Alzheimer neurodegeneration.
Contrast With Compression Therapy Enhances Muscle Function Recovery and Attenuates Glycogen Disruption After Exercise.
Antidiabetic efficacy of Trifolium alexandrinum extracts hesperetin and quercetin in ameliorating carbohydrate metabolism and activating IR and AMPK signaling in the pancreatic tissues of diabetic rats.
Safety and effectiveness of resistance training in patients with late onset Pompe disease - a pilot study.
Case Report: Hepatic Adenomatosis in a Patient With Prader-Willi Syndrome.
Atrial Lesions in a Pedigree With PRKAG2 Cardiomyopathy: Involvement of Disrupted AMP-Activated Protein Kinase Signaling.
L-alanine supplementation in Pompe disease (IOPD): a potential therapeutic implementation for patients on ERT? A case report.
eEF2K promotes PD-L1 stabilization through inactivating GSK3β in melanoma.

Eur J Appl Physiol. 2022 Mar 30.

A century of exercise physiology: key concepts in regulation of glycogen metabolism in skeletal muscle.

Abram Katz.

  Glycogen is a branched, glucose polymer and the storage form of glucose in cells. Glycogen has traditionally been viewed as a key substrate for muscle ATP production during conditions of high energy demand and considered to be limiting for work capacity and force generation under defined conditions. Glycogenolysis is catalyzed by phosphorylase, while glycogenesis is catalyzed by glycogen synthase. For many years, it was believed that a primer was required for de novo glycogen synthesis and the protein considered responsible for this process was ultimately discovered and named glycogenin. However, the subsequent observation of glycogen storage in the absence of functional glycogenin raises questions about the true role of the protein. In resting muscle, phosphorylase is generally considered to be present in two forms: non-phosphorylated and inactive (phosphorylase b) and phosphorylated and constitutively active (phosphorylase a). Initially, it was believed that activation of phosphorylase during intense muscle contraction was primarily accounted for by phosphorylation of phosphorylase b (activated by increases in AMP) to a, and that glycogen synthesis during recovery from exercise occurred solely through mechanisms controlled by glucose transport and glycogen synthase. However, it now appears that these views require modifications. Moreover, the traditional roles of glycogen in muscle function have been extended in recent years and in some instances, the original concepts have undergone revision. Thus, despite the extensive amount of knowledge accrued during the past 100 years, several critical questions remain regarding the regulation of glycogen metabolism and its role in living muscle.

Keywords:  Exercise; Glycogen; Glycogen synthase; Glycogenin; Muscle; Phosphorylase

DOI:  https://doi.org/10.1007/s00421-022-04935-1
Sci Rep. 2022 Mar 29. 12(1): 5327

Altered electrical properties in skeletal muscle of mice with glycogen storage disease type II.

Janice A Nagy, Carson Semple, Daniela Riveros, Benjamin Sanchez, Seward B Rutkove.

Electrical impedance methods, including electrical impedance myography, are increasingly being used as biomarkers of muscle health since they measure passive electrical properties of muscle that alter in disease. One disorder, Pompe Disease (Glycogen storage disease type II (GSDII)), remains relatively unstudied. This disease is marked by dramatic accumulation of intracellular myofiber glycogen. Here we assessed the electrical properties of skeletal muscle in a model of GSDII, the Pompe6neo/6neo (Pompe) mouse. Ex vivo impedance measurements of gastrocnemius (GA) were obtained using a dielectric measuring cell in 30-week-old female Pompe (N = 10) and WT (N = 10) mice. Longitudinal and transverse conductivity, σ, and the relative permittivity, εr, and Cole-Cole complex resistivity parameters at 0 Hz and infinite frequency, ρo and ρ∞, respectively, and the intracellular resistivity, ρintracellular were determined from the impedance data. Glycogen content (GC) was visualized histologically and quantified biochemically. At frequencies > 1 MHz, Pompe mice demonstrated significantly decreased longitudinal and transverse conductivity, increased Cole-Cole parameters, ρo and ρo-ρ∞, and decreased ρintracellular. Changes in longitudinal conductivity and ρintracellular correlated with increased GC in Pompe animals. Ex vivo high frequency impedance measures are sensitive to alterations in intracellular myofiber features considered characteristic of GSDII, making them potentially useful measures of disease status.

DOI: https://doi.org/10.1038/s41598-022-09328-0
Neurotherapeutics. 2022 Mar 28.

AAV-Mediated Artificial miRNA Reduces Pathogenic Polyglucosan Bodies and Neuroinflammation in Adult Polyglucosan Body and Lafora Disease Mouse Models.

Emrah Gumusgoz, Sahba Kasiri, Dikran R Guisso, Jun Wu, Matthew Dear, Brandy Verhalen, Berge A Minassian.

  Adult polyglucosan body disease (APBD) and Lafora disease (LD) are autosomal recessive glycogen storage neurological disorders. APBD is caused by mutations in the glycogen branching enzyme (GBE1) gene and is characterized by progressive upper and lower motor neuron dysfunction and premature death. LD is a fatal progressive myoclonus epilepsy caused by loss of function mutations in the EPM2A or EPM2B gene. These clinically distinct neurogenetic diseases share a common pathology. This consists of time-dependent formation, precipitation, and accumulation of an abnormal form of glycogen (polyglucosan) into gradually enlarging inclusions, polyglucosan bodies (PBs) in ever-increasing numbers of neurons and astrocytes. The growth and spread of PBs are followed by astrogliosis, microgliosis, and neurodegeneration. The key defect in polyglucosans is that their glucan branches are longer than those of normal glycogen, which prevents them from remaining in solution. Since the lengths of glycogen branches are determined by the enzyme glycogen synthase, we hypothesized that downregulating this enzyme could prevent or hinder the generation of the pathogenic PBs. Here, we pursued an adeno-associated virus vector (AAV) mediated RNA-interference (RNAi) strategy. This approach resulted in approximately 15% reduction of glycogen synthase mRNA and an approximately 40% reduction of PBs across the brain in the APBD and both LD mouse models. This was accompanied by improvements in early neuroinflammatory markers of disease. This work represents proof of principle toward developing a single lifetime dose therapy for two fatal neurological diseases: APBD and LD. The approach is likely applicable to other severe and common diseases of glycogen storage.

Keywords:  AAV9; APBD; EPM2A; EPM2B; GBE1; GYS1; RNAi; miRNA

DOI:  https://doi.org/10.1007/s13311-022-01218-7
EBioMedicine. 2022 Mar 24. pii: S2352-3964(22)00154-2. [Epub ahead of print]78 103970

Human tau accumulation promotes glycogen synthase kinase-3β acetylation and thus upregulates the kinase: A vicious cycle in Alzheimer neurodegeneration.

Qiuzhi Zhou, Shihong Li, Mengzhu Li, Dan Ke, Qun Wang, Ying Yang, Gong-Ping Liu, Xiao-Chuan Wang, Enjie Liu, Jian-Zhi Wang.

   BACKGROUND: Glycogen synthase kinase-3β (GSK-3β) is one of the most effective kinases in promoting tau hyperphosphorylation and accumulation in Alzheimer's disease (AD). However, it is not clear how GSK-3β activity is regulated during AD progression.
METHODS: We firstly used mass spectrometry to identify the acetylation site of GSK-3β, and then established the cell and animal models of GSK-3β acetylation. Next, we conducted molecular, cell biological and behavioral tests. Finally, we designed a peptide to test whether blocking tau-mediated GSK-3β acetylation could be beneficial to AD.
FINDINGS: We found that GSK-3β protein levels increased in the brains of AD patients and the transgenic mice. Overexpressing tau increased GSK-3β protein level with increased acetylation and decreased ubiquitination-related proteolysis. Tau could directly acetylate GSK-3β at K15 both in vitro and in vivo. K15-acetylation inhibited ubiquitination-associated proteolysis of GSK-3β and changed its activity-dependent phosphorylation, leading to over-activation of the kinase. GSK-3β activation by K15-acetylation in turn exacerbated the AD-like pathologies. Importantly, competitively inhibiting GSK-3β K15-acetylation by a novel-designed peptide remarkably improved cognitive impairment and the AD-like pathologies in 3xTg-AD mice.
INTERPRETATION: Tau can directly acetylate GSK-3β at K15 which reveals a vicious cycle between tau hyperphosphorylation and GSK-3β activation.
FUNDING: This study was supported in parts by grants from Science and Technology Committee of China (2016YFC1305800), Hubei Province (2018ACA142), Natural Science Foundation of China (91949205, 82001134, 31730035, 81721005), Guangdong Provincial Key S&T Program (018B030336001).

Keywords:  Acetylation; Alzheimer's disease; Glycogen synthase kinase-3β; Inhibitory peptide; Proteolysis; Tau

DOI:  https://doi.org/10.1016/j.ebiom.2022.103970
Sports Health. 2022 Mar 27. 19417381221080172

Contrast With Compression Therapy Enhances Muscle Function Recovery and Attenuates Glycogen Disruption After Exercise.

Vincent M Colantuono, Ryan Oakley, Disa L Hatfield, Luis Penailillo, Shabnam Lateef, Jacob E Earp.

   BACKGROUND: Exercise-associated muscle damage (EAMD) temporally impairs muscle function and intramuscular glycogen storage. Contrast with compression (CwC) therapy provides localized EAMD treatment with minimal changes in core/tissue temperature that can impair glycogen resynthesis.
HYPOTHESIS: CwC will enhance the recovery of strength, power, and joint mobility, reduce markers of EAMD, and attenuate the disruption of glycogen storage observed after damaging exercise.
STUDY DESIGN: Randomized controlled trial with crossover design.
LEVEL OF EVIDENCE: Level 2.
METHODS: Ten men completed 2 bouts of eccentric elbow flexor exercise, separated by 1 week, using contralateral arms. After each bout, participants received either CwC therapy (at 0, 24, and 48 h postexercise) or no therapy with intervention order and limb randomly assigned. Prior to (pre-exercise) and 1, 24, 48, and 72 h after each exercise bout, muscular strength, muscular power, intramuscular glycogen, creatine kinase, muscle thickness, muscle soreness, pressure pain threshold, active elbow flexion, passive elbow extension, and dietary intake were assessed. Comparisons were made between conditions over time (interaction effects) using separate repeated-measures analyses of variance/multivariate analyses of variance and effect sizes (Cohen d) to describe treatment effect at each time point.
RESULTS: Significant interaction effects were observed for muscular strength (d = 0.67-1.12), muscular power (d = 0.20-0.65), intramuscular glycogen (d = 0.29-0.81), creatine kinase (d = 0.01-0.96), muscle thickness (d = 0.35-0.70), muscle soreness (d = 0.18-0.85), and active elbow flexion (d = 0.65-1.17) indicating a beneficial effect of CwC over time (P ≤ 0.05). In contrast, no significant interaction effect was observed for pressure pain threshold or passive elbow extension (P > 0.05).
CONCLUSION: These results support the use of CwC for the recovery of muscle function after damaging exercise in male patients and indicate that CwC attenuates, but does not remove, the disruption of intramuscular glycogen stores observed after intense eccentric exercise.
CLINICAL RELEVANCE: Glycolysis-dependent athletes may benefit from CwC therapy after training/competition that causes EAMD.

Keywords:  contrast therapy; cryotherapy; echo-intensity; muscle damage; recovery

DOI:  https://doi.org/10.1177/19417381221080172
Biomed Pharmacother. 2022 Mar 25. pii: S0753-3322(22)00226-8. [Epub ahead of print]149 112838

Antidiabetic efficacy of Trifolium alexandrinum extracts hesperetin and quercetin in ameliorating carbohydrate metabolism and activating IR and AMPK signaling in the pancreatic tissues of diabetic rats.

Heba M Abdou, Fatma A Hamaad, Esraa Y Ali, Mamdooh H Ghoneum.

  Diabetes is a metabolic disease that is mainly characterized by hyperglycemia. The present work investigated the efficacy of the flavanones hesperetin (HES) and quercetin (Q) extracted from Trifolium alexandrinum (TA) to treat type 2 diabetic rats. Wistar albino rats were supplemented with a high fat diet (HFD) for 2 weeks and then administered streptozotocin to induce diabetes. Diabetic rats were orally treated with Q, HES, and TA extract at concentrations of 40, 50, and 200 mg/kg BW, respectively, for 4 weeks. Various biochemical, molecular, and histological analysis were performed to evaluate the antidiabetic effects of these treatments. Q, HES, and TA extract treatments all significantly improved diabetic rats' levels of serum glucose, insulin, glucagon, liver function enzymes, hepatic glycogen, α-amylase, lipase enzymes, lipid profiles, oxidative stress indicators, and antioxidant enzymes as compared with control diabetic untreated rats. In addition, supplementation with Q, HES, and TA extract attenuated the activities of glucose-6-phosphate; fructose-1,6-bisphospahate; 6-phosphogluconate dehydrogenase; glucose-6-phosphate dehydrogenase; glucokinase; and hexokinase in pancreatic tissue, and they improved the levels of glucose transporter 2 and glucose transporter 4. Furthermore, these treatments modulated the expressions levels of insulin receptor (IR), phosphoinositide 3-kinase (PI3K), AMP-activated protein kinase (AMPK), caspase-3, and interleukin-1β (IL-1β). Enhancement of the histological alterations in pancreatic tissues provided further evidence of the ability of Q, HES, and TA extract to exert antidiabetic effects. Q, HES, and TA extract remedied insulin resistance by altering the IR/PI3K and AMPK signaling pathways, and they attenuated type 2 diabetes by improving the antioxidant defense system.

Keywords:  AMPK; Glucose metabolism; Hesperetin; High fat diet; IR; Quercetin; Trifolium alexandrinum (TA) extract

DOI:  https://doi.org/10.1016/j.biopha.2022.112838
Neuromuscul Disord. 2022 Feb 17. pii: S0960-8966(22)00035-9. [Epub ahead of print]

Safety and effectiveness of resistance training in patients with late onset Pompe disease - a pilot study.

Caleb Bhatnagar, Jeet Shah, Bhumi Ramani, Abhilasha Surampalli, Mahima Avanti, Shlomit Radom-Aizik, Margaret Knight, Lan Weiss, Vince Caiozzo, Virginia Kimonis.

  Pompe disease is a progressive myopathy resulting from deficiency in lysosomal enzyme acid α-glucosidase (GAA), which leads to glycogen accumulation in lysosomes primarily in skeletal and cardiac muscle. Enzyme replacement therapy (ERT) with recombinant human (rh) GAA works well in alleviating the cardiomyopathy; however, many patients continue to have progressive muscle weakness. The purpose of this study was to evaluate the effectiveness of a respiratory training combined with 24-week supervised resistance training program on muscle strength (measured by Biodex)), and respiratory function including maximum inspiratory pressure (MIP), maximum expiratory pressure (MEP) in subjects with late onset Pompe disease receiving ERT. Ten subjects participated in a 24-week resistance exercise program, three times per week, in addition to respiratory muscle exercise training six days per week. Overall, at the end of the resistance training program, as measured by Biodex dynamometry, the leg extensor strength improved by 10.5 ± 3.2Nm. (<p 0.01), leg flexors improved by 12.1 ± 4.1Nm (p < 0.01), the elbow flexors improved by 5.1 ± 2.3Nm (p = 0.03), and the elbow extensor strength improved by a mean of 4.5 ± 1.9Nm. (p = 0.02). MIP improved by 8.5 ± 3.7 cm H2O (p = 0.03) and the MEP by 6.4 ± 4.4 (p = 0.16). The exercise training significantly improved the trajectories of MIP and 6 MWT outcomes but not FVC when compared with the natural history data available in 6 individuals. These pilot results indicate that resistance training combined with respiratory training and ERT had a positive effect on muscular strength, functional capacity, and respiratory function in patients with late-onset Pompe disease and might be considered as a potential adjunct therapy in this population.

Keywords:  Exercise; Neuromuscular; Pompe disease; Resistance

DOI:  https://doi.org/10.1016/j.nmd.2022.02.002
Front Endocrinol (Lausanne). 2022 ;13 826772

Case Report: Hepatic Adenomatosis in a Patient With Prader-Willi Syndrome.

Hajar Dauleh, Ali Soliman, Basma Haris, Amal Khalifa, Noor Al Khori, Khalid Hussain.

  Prader-Willi syndrome (PWS) is a genetic disorder caused by the lack of expression of genes on the paternally inherited chromosome region 15q11.2-q13. It is a multisystem disorder that is characterized by severe hypotonia with poor suck and feeding difficulties in early infancy, followed in early childhood by excessive eating and gradual development of morbid obesity. The incidence of type 2 diabetes mellitus is high, particularly in obese patients. Non-alcoholic fatty liver disease has also been reported in some patients with PWS. Liver adenomatosis is a benign vascular lesion of the liver, defined by the presence of >10 adenomas, in the otherwise healthy liver parenchyma. We report the first case of a patient with PWS with severe obesity, type 2 diabetes mellitus, and non-alcoholic fatty liver who also developed liver adenomatosis, review the pediatric literature on liver adenomatosis, and discuss the potential underlying mechanisms.

Keywords:  Glycogen Storage Disease; Prader Willi syndrom; hepatic adenomatosis; liver adenoma; oral contraception pills

DOI:  https://doi.org/10.3389/fendo.2022.826772
Front Cardiovasc Med. 2022 ;9 840337

Atrial Lesions in a Pedigree With PRKAG2 Cardiomyopathy: Involvement of Disrupted AMP-Activated Protein Kinase Signaling.

Shaojie Chen, Yongping Lin, Yue Zhu, Le Geng, Chang Cui, Zhaomin Li, Hailei Liu, Hongwu Chen, Weizhu Ju, Minglong Chen.

  PRKAG2 cardiomyopathy is a rare progressive disease characterized by increased ventricular wall thickness and preexcitation. Dysfunction of the protein 5'-AMP-activated protein kinase (AMPK) plays a decisive role in the progression of ventricular lesions. Although patients with the PRKAG2-R302Q mutation have a high incidence of atrial fibrillation (AF), the molecular mechanism contributing to the disease remains unclear. We carried out whole-genome sequencing with linkage analysis in three affected members of a family. Atrial samples were obtained from the proband via surgical intervention. Control atrium biopsies were obtained from patients with persistent AF. Pathological changes were analyzed using the hematoxylin and eosin (H&E), Masson, and periodic acid-Schiff (PAS) staining. The AMPK signaling pathway was investigated by western blot. A murine atrial cardiomyocyte cell line (HL-1) and human induced pluripotent stem derived atrial cardiomyocytes (hiPSC-ACMs) were transfected with an adenovirus carrying the same mutation. We used enzyme linked immunosorbent assay (ELISA) to determine the AMPK activity in HL-1 cells and hiPSC-ACMs overexpressing PRKAG2-R302Q. Pathological results showed a large quantity of glycogen accumulation and vacuolization in cardiomyocytes from the proband atrial tissue. Western blot analysis revealed that the AMPK activity was significantly downregulated compared with that of the controls. Furthermore, remarkable glycogen deposition and impairment of AMPK activity were reproduced in HL-1 cells overexpressing PRKAG2-R302Q. Taken together, PRKAG2-R302Q mutation directly impair atrial cardiomyocytes. PRKAG2-R302Q mutation lead to glycogen deposition and promote the growth of atrial lesions by disrupting the AMPK pathway.

Keywords:  PRKAG2; atrial arrhythmia; glycogen deposition; histology; pedigree

DOI:  https://doi.org/10.3389/fcvm.2022.840337
Ital J Pediatr. 2022 Mar 28. 48(1): 48

L-alanine supplementation in Pompe disease (IOPD): a potential therapeutic implementation for patients on ERT? A case report.

Valentina Rovelli, Juri Zuvadelli, Marta Piotto, Andrea Scopari, Alice Re Dionigi, Vittoria Ercoli, Sabrina Paci, Graziella Cefalo, Elisabetta Salvatici, Giuseppe Banderali.

   BACKGROUND: Pompe disease (PD) is a disorder of glycogen metabolism conditioning a progressive and life conditioning myopathy. Enzyme replacement therapy (ERT) is currently the best treatment option for PD, but is not resolutive. While other potential therapeutic approaches have been reported before, these have never been tried as co- treatments. L-alanine oral supplementation (LAOS) has been proven to reduce muscle breakdown: we hereby report the first case of supplementation on a PD patient on ERT.
CASE PRESENTATION: F. is a 9 y.o. infantile onset Pompe Disease (IOPD) girl ERT-treated since age 1 developing a progressive myopathy. We started her on LAOS and performed assessments at baseline, 6 and 9 months. At baseline, F.'s weight, height and BMI were within normal ranges, while body composition showed low fat mass -FM and high resting energy expenditure-REE levels. After LAOS, a progressive FM increase and REE reduction could be observed both at 6 and 9 months.
CONCLUSIONS: ERT is not curative for PD patients thus additional treatments could be considered to improve outcomes. Our patient showed physical signs of inability to accumulate energy when exclusively on ERT, while FM increase and REE reduction occurred when supplemented with LAOS, likely reflecting anabolic pathways' implementation. This is the first case reporting potential LAOS benefits in PD-on ERT patients. Longitudinal case control studies are yet needed to evaluate possible efficacy of combined LAOS And ERT treatment in PD patients.

Keywords:  Body composition; Enzyme replacement therapy; L-alanine; Myopathy; Pompe Disease

DOI:  https://doi.org/10.1186/s13052-022-01249-y
J Immunother Cancer. 2022 Mar;pii: e004026. [Epub ahead of print]10(3):

eEF2K promotes PD-L1 stabilization through inactivating GSK3β in melanoma.

Xisha Chen, Kuansong Wang, Shilong Jiang, Hongyin Sun, Xuanling Che, Minghui Zhang, Jiaying He, Ying Wen, Mengting Liao, Xiangling Li, Xiaoming Zhou, Jianxun Song, Xingcong Ren, Wenjun Yi, Jinming Yang, Xiang Chen, Mingzhu Yin, Yan Cheng.

   BACKGROUND: Immune checkpoint blockade (ICB) targeting programmed death ligand-1 (PD-L1)/programmed cell death protein-1 (PD-1) pathway has become an attractive strategy for cancer treatment; however, unsatisfactory efficacy has limited its clinical benefits. Therefore, a more comprehensive understanding of the regulation of PD-L1 expression is essential for developing more effective cancer immunotherapy. Recent studies have revealed the important roles of eukaryotic elongation factor 2 kinase (eEF2K) in promoting epithelial-mesenchymal transition (EMT), angiogenesis, tumor cell migration and invasion; nevertheless, the exact role of eEF2K in the regulation of tumor immune microenvironment (TIME) remains largely unknown.
METHODS: In this study, we used a cohort of 38 patients with melanoma who received anti-PD-1 treatment to explore the association between eEF2K expression and immunotherapy efficacy against melanoma. Immunoprecipitation-mass spectrometry analysis and in vitro assays were used to examine the role and molecular mechanism of eEF2K in regulating PD-L1 expression. We also determined the effects of eEF2K on tumor growth and cytotoxicity of CD8+ T cells in TIME in a mouse melanoma model. We further investigated the efficacy of the eEF2K inhibition in combination with anti-PD-1 treatment in vivo.
RESULTS: High eEF2K expression is correlated with better therapeutic response and longer survival in patients with melanoma treated with PD-1 monoclonal antibody (mAb). Moreover, eEF2K protein expression is positively correlated with PD-L1 protein expression. Mechanistically, eEF2K directly bound to and inactivated glycogen synthase kinase 3 beta (GSK3β) by phosphorylating it at serine 9 (S9), leading to PD-L1 protein stabilization and upregulation, and subsequently tumor immune evasion. Knockdown of eEF2K decreased PD-L1 expression and enhanced CD8+ T cell activity, thus dramatically attenuating murine B16F10 melanoma growth in vivo. Clinically, p-GSK3β/S9 expression is positively correlated with the expressions of eEF2K and PD-L1, and the response to anti-PD-1 immunotherapy. Furthermore, eEF2K inhibitor, NH125 treatment or eEF2K knockdown enhanced the efficacy of PD-1 mAb therapy in a melanoma mouse model.
CONCLUSIONS: Our results suggest that eEF2K may serve as a biomarker for predicting therapeutic response and prognosis in patients receiving anti-PD-1 therapy, reveal a vital role of eEF2K in regulating TIME by controlling PD-L1 expression and provide a potential combination therapeutic strategy of eEF2K inhibition with ICB therapy.

Keywords:  biomarkers, tumor; drug therapy, combination; immunotherapy; melanoma; tumor microenvironment

DOI:  https://doi.org/10.1136/jitc-2021-004026