Immune Checkpoint Molecules and Glucose Metabolism in HIV-Induced T Cell Exhaustion

Chan, Yee Teng; Cheong, Heng Choon; Tang, Ting; Rajasuriar, Reena; Cheng, Kun; Looi, Chung Yeng; Wong, Won Fen; Kamarulzaman, Adeeba

doi:10.3390/biomedicines10112809

Cited by 9 publications

(6 citation statements)

References 138 publications

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“…Blocking inhibitory receptors such as PD-1, CTLA-4 or Lag-3 have reversed this exhausted state in clinical trials of T cells in cancer [88]. Additionally, metformin has been utilized in HIV-induced T cell exhaustion treatment to increase glucose import and subsequent cellular energy production [89]. Meanwhile, knocking out CD36 in Tregs of a hypoxic tumor microenvironment allowed lymphocytes to kill target cells while sustaining homeostasis, pointing to the importance of considering metabolic components like these in therapeutic treatments [90].…”

Section: Implications Of Altered Lipid Metabolism In Me/cfs T Cellsmentioning

confidence: 99%

Altered Fatty Acid Oxidation in Lymphocyte Populations of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Maya

Leddy

Gottschalk³

et al. 2023

IJMS

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Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling multisystem illness in which individuals are plagued with fatigue, inflammatory symptoms, cognitive dysfunction, and the hallmark symptom, post-exertional malaise. While the cause of this disease remains unknown, there is evidence of a potential infectious component that, along with patient symptoms and common onsets of the disease, implicates immune system dysfunction. To further our understanding of the state of ME/CFS lymphocytes, we characterized the role of fatty acids in isolated Natural Killer cells, CD4+ T cells, and CD8+ T cells in circulation and after overnight stimulation, through implicit perturbations to fatty acid oxidation. We examined samples obtained from at least 8 and as many as 20 subjects for immune cell fatty acid characterization in a variety of experiments and found that all three isolated cell types increased their utilization of lipids and levels of pertinent proteins involved in this metabolic pathway in ME/CFS samples, particularly during higher energy demands and activation. In T cells, we characterized the cell populations contributing to these metabolic shifts, which included CD4+ memory cells, CD4+ effector cells, CD8+ naïve cells, and CD8+ memory cells. We also discovered that patients with ME/CFS and healthy control samples had significant correlations between measurements of CD4+ T cell fatty acid metabolism and demographic data. These findings provide support for metabolic dysfunction in ME/CFS immune cells. We further hypothesize about the consequences that these altered fuel dependencies may have on T and NK cell effector function, which may shed light on the illness’s mechanism of action.

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Section: Implications Of Altered Lipid Metabolism In Me/cfs T Cellsmentioning

confidence: 99%

Altered Fatty Acid Oxidation in Lymphocyte Populations of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Maya

Leddy

Gottschalk³

et al. 2023

IJMS

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“…With regard to the use of anti-PD-1/PD-L1 as adjuvants, a difference in efficacy may be influenced by various factors, such as the type of antigen and underlying mechanisms of protective responses. Moreover, several pathways aside from the PD-1/PD-L1 axis are involved in the establishment of T cell exhaustion and include the expression of other molecules, such as cytotoxic T-lymphocyte antigen-4 (CTLA-4), TIM-3, LAG-3 and T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) that all regulate T cell function through independent mechanisms [ 30 ]. Thus, the combination of antibodies to target different T cell exhaustion pathways may be more effective than the use of individual antibody treatment.…”

Section: Discussionmentioning

confidence: 99%

Ex Vivo Blockade of the PD-1 Pathway Improves Recall IFNγ Responses of HIV-Infected Persons on Antiretroviral Therapy

et al. 2023

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Despite antiretroviral therapy (ART), immune exhaustion persists in HIV infection and limits T cell responses to HIV or other pathogens. Moreover, HIV infection results in the loss of pre-existing immunity. Here, we investigated the effect of blocking the PD-1 pathway on recall IFNγ responses to tetanus toxoid (TT) and measles virus (MV) antigens in HIV-infected persons on ART with prior TT and MV immunity. The ex vivo treatment of lymphocytes with anti-PD-1 and anti-PD-L1 antibodies significantly increased TT- and MV-specific IFNγ responses. The responses to TT and MV antigens alone or in combination with antibodies blocking the PD-1 pathway positively correlated with CD4 T cell levels. Furthermore, T cell PD-1 expression levels inversely correlated with recall IFNγ responses in combination with antibodies blocking the PD-1 pathway but not with IFNγ responses to antigens only. Our study suggested that targeting the PD-1 pathway may boost vaccine-induced pre-existing immunity in HIV-infected persons on ART depending on the degree of immune exhaustion.

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“…Recent studies have found that T-cell dysfunction is associated with glucose metabolism disorders [44], and the competition between tumor cells and CD8 + T cells for limited glucose leads to reduced CD8 + Tcell effector function [45]. However, Chang et al found that in exhausted CD8 + T cells in vitro, it was di cult to increase their effector capacity even if superphysiological levels of glucose were given [46].…”

Section: Discussionmentioning

confidence: 99%

Multiomics reveals the role of ENO1 in bladder cancer and constructs an epithelial-related prognostic model to predict prognosis and efficacy

Su,

You,

et al. 2023

Preprint

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Background α-Enolase (ENO1) is a crucial molecular target for tumor therapy and has emerged as a research hotspot in recent decades. Here, we aimed to explore the role of ENO1 in bladder cancer (BLCA) and then construct a signature to predict the prognosis and treatment response of BLCA.Methods Differential expression, prognosis analysis and in vitro cell experiments were used to reveal the value of ENO1 in BLCA. The R package "Seurat" was used for single-cell RNA sequence (scRNA-seq) data processing. The R package “singleR” and cellMarker website were used to annotate cells. The FindAllMarkers function and “limma” were used to screen hub genes. Univariate Cox and least absolute shrinkage and selection operator (LASSO) analyses were used to construct the signature. Differences in prognosis and treatment between high- and low-risk groups were investigated.Results ENO1 was highly expressed in BLCA tissues, as verified by IHC, and was associated with poor prognosis. The analysis of the tumor immune microenvironment by bulk sequencing and scRNA-seq showed that ENO1 was associated with CD8 + T-cell exhaustion. Additionally, the in vitro results showed that ENO1 could promote the proliferation and invasion of BLCA cells. Then, the analysis of epithelial cells (ECs) revealed that ENO1 might promote BLCA progression by metabolism, the cell cycle and some carcinogenic pathways. A total of 249 hub genes were obtained from differentially expressed genes between ENO1-related ECs, and we used LASSO analysis to construct a novel signature that not only accurately predicted the prognosis of BLCA patients but also predicted the response to treatment for BLCA. Finally, we constructed a nomogram to better guide clinical application.Conclusion Through multiomics analysis, we found that ENO1 was overexpressed in bladder cancer and associated with poor prognosis, CD8 + T-cell exhaustion and epithelial heterogeneity. Finally, the prognosis and treatment of patients can be well predicted by constructing an epithelial cell prognostic signature.

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Immune Checkpoint Molecules and Glucose Metabolism in HIV-Induced T Cell Exhaustion

Cited by 9 publications

References 138 publications

Altered Fatty Acid Oxidation in Lymphocyte Populations of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Altered Fatty Acid Oxidation in Lymphocyte Populations of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Ex Vivo Blockade of the PD-1 Pathway Improves Recall IFNγ Responses of HIV-Infected Persons on Antiretroviral Therapy

Multiomics reveals the role of ENO1 in bladder cancer and constructs an epithelial-related prognostic model to predict prognosis and efficacy

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