Sildenafil, a Type-5 Phosphodiesterase Inhibitor, Fails to Reverse Myeloid-Derived Suppressor Cell-Mediated T Cell Suppression in Cells Isolated From Tuberculosis Patients

Leukes, Vinzeigh N.; Malherbe, Stephanus T.; Hiemstra, Andriëtte; Kotze, Leigh A.; Roos, K. R.; Keyser, Alana; Swardt, Dalene de; Gutschmidt, Andrea; Walzl, Gerhard; Plessis, Nelita du

doi:10.3389/fimmu.2022.883886

Cited by 3 publications

(3 citation statements)

References 67 publications

(75 reference statements)

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“…Combining PDE-5i sildenafil with antituberculosis basal therapy improved treatment efficacy because PDE-5i sildenafil increased cyclic adenosine monophosphate (cGMP) in MDSCs, leading to a decrease in Arg-1 and nitric oxide synthase 2 (NOS2), thereby decreasing the mechanism of MDSCs-induced T-cell suppression (74). However, Vinzeigh N et al demonstrated that sildenafil was incapable of reversing MDSCs-mediated T-cell suppression and had little effect on enhancing host immunity (77). The above findings for MDSCstargeted therapy suggest that MDSCs may be a new target for antituberculosis host-directed therapy, but the results are contradictory and additional investigation is required.…”

Section: Tuberculosismentioning

confidence: 99%

“…However, Vinzeigh N et al. demonstrated that sildenafil was incapable of reversing MDSCs-mediated T-cell suppression and had little effect on enhancing host immunity ( 77 ). The above findings for MDSCs-targeted therapy suggest that MDSCs may be a new target for anti-tuberculosis host-directed therapy, but the results are contradictory and additional investigation is required.…”

Section: Mdscs As a Target For Infectious Lung Diseasesmentioning

confidence: 99%

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Advances in the study of myeloid-derived suppressor cells in infectious lung diseases

Zhang

Yuan

2023

Front. Immunol.

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Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature cells capable of inhibiting T-cell responses. MDSCs have a crucial role in the regulation of the immune response of the body to pathogens, especially in inflammatory response and pathogenesis during anti-infection. Pathogens such as bacteria and viruses use MDSCs as their infectious targets, and even some pathogens may exploit the inhibitory activity of MDSCs to enhance pathogen persistence and chronic infection of the host. Recent researches have revealed the pathogenic significance of MDSCs in pathogens such as bacteria and viruses, despite the fact that the majority of studies on MDSCs have focused on tumor immune evasion. With the increased prevalence of viral respiratory infections, the resurgence of classical tuberculosis, and the advent of medication resistance in common bacterial pneumonia, research on MDSCs in these illnesses is intensifying. The purpose of this work is to provide new avenues for treatment approaches to pulmonary infectious disorders by outlining the mechanism of action of MDSCs as a biomarker and therapeutic target in pulmonary infectious diseases.

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Section: Tuberculosismentioning

confidence: 99%

Section: Mdscs As a Target For Infectious Lung Diseasesmentioning

confidence: 99%

Advances in the study of myeloid-derived suppressor cells in infectious lung diseases

Zhang

Yuan

2023

Front. Immunol.

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“…Tasquinimod causes exhaustion of MDSC, and has been shown to enhance mycobacterial clearance in mice ( 63 ). Both sildenafil and ATRA initially showed promise as TB host directed therapies, but recent data using human MDSC have been disappointing ( 64 , 65 ). Many of these MDSC-targeting therapies have been identified as possible treatments for COVID-19, but little data is available on their efficacy ( 66 ).…”

Section: Suppressive Myeloid Cellsmentioning

confidence: 99%

Suppressive myeloid cells in SARS-CoV-2 and Mycobacterium tuberculosis co-infection

et al. 2023

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Epidemiologic data show that both current and previous tuberculosis (TB) increase the risk of in-hospital mortality from coronavirus disease-2019 (COVID-19), and there is a similar trend for poor outcomes from Mycobacterium tuberculosis (Mtb) infection after recent SARS-CoV-2. A shared dysregulation of immunity explains the dual risk posed by co-infection, but the specific mechanisms are being explored. While initial attention focused on T cell immunity, more comprehensive analyses revealed a dysfunctional innate immune response in COVID-19, characterized by reduced numbers of dendritic cells, NK cells and a redistribution of mononuclear phagocytes towards intermediate myeloid subsets. During hyper- or chronic inflammatory processes, activation signals from molecules such as growth factors and alarmins lead to the expansion of an immature population of myeloid cells called myeloid-deprived suppressor cells (MDSC). These cells enter a state of pathological activation, lose their ability to rapidly clear pathogens, and instead become broadly immunosuppressive. MDSC are enriched in the peripheral blood of patients with severe COVID-19; associated with mortality; and with higher levels of inflammatory cytokines. In TB, MDSC have been implicated in loss of control of Mtb in the granuloma and ineffective innate and T cell immunity to the pathogen. Considering that innate immune sensing serves as first line of both anti-bacterial and anti-viral defence mechanisms, we propose MDSC as a crucial mechanism for the adverse clinical trajectories of TB-COVID-19 coinfection.

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PDE5 inhibitors against cancer via mediating immune cells in tumor microenvironment: AI‐based approach for future drug repurposing exploration

Zhang,

Huang,

Feng

et al. 2024

Interdisciplinary Medicine

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Phosphodiesterase‐5 (PDE5) inhibitors are used clinically for the treatment of erectile dysfunction, pulmonary arterial hypertension, and other urological diseases. Emerging evidences have suggested the therapeutic capacity of PDE5 inhibitors as the repurposed drugs in oncology. However, the essential immune function of PDE5 inhibitors against cancer in tumor microenvironment (TME) remains unclear. This review aimed to summarize the recent advances regarding the repurposing of PDE5 inhibitors as anti‐cancer agents for cancer management to enhance the anti‐tumor immune response by mediating various immune cells, which included the myeloid‐derived suppressor cells, macrophages, T cells, fibroblasts, and natural killer cells in TME. Moreover, artificial intelligence (AI), as a new approach, is composed of traditional machine learning and deep learning methods and could be potentially used to identify the targets of immune cells in TME and predict the efficacy for repurposed drug toward malignancies. In summary, these endeavors provide novel insights into the comprehensive strategies for PDE5 inhibitors mediating immune cells against cancer and AI‐based approach for future drug repurposing exploration.

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Sildenafil, a Type-5 Phosphodiesterase Inhibitor, Fails to Reverse Myeloid-Derived Suppressor Cell-Mediated T Cell Suppression in Cells Isolated From Tuberculosis Patients

Cited by 3 publications

References 67 publications

Advances in the study of myeloid-derived suppressor cells in infectious lung diseases

Advances in the study of myeloid-derived suppressor cells in infectious lung diseases

Suppressive myeloid cells in SARS-CoV-2 and Mycobacterium tuberculosis co-infection

PDE5 inhibitors against cancer via mediating immune cells in tumor microenvironment: AI‐based approach for future drug repurposing exploration

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