Immunomodulatory Effects of Drugs for Effective Cancer Immunotherapy

Matsushita, Maiko; Kawaguchi, Mai

doi:10.1155/2018/8653489

Cited by 32 publications

(20 citation statements)

References 69 publications

(50 reference statements)

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“…The downmodulation of such ligands represent one of the mechanisms of immune-evasion for many tumors, including NB [4]. Anticancer drugs with immune-modulating effects can induce the immune system to attack cancer cells at a relatively low dose, thus contributing to better outcomes in cancer patients [38]. Several are the drug-mediated molecular mechanisms underlying the upregulation of activating ligands, representing efficient strategies aimed to boost the NK cell-based anti-tumor immunotherapy [9].…”

Section: Discussionmentioning

confidence: 99%

The BET-bromodomain inhibitor JQ1 renders neuroblastoma cells more resistant to NK cell-mediated recognition and killing by downregulating ligands for NKG2D and DNAM-1 receptors

et al. 2019

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Low expression of ligands for NK cell-activating receptors contributes to neuroblastoma (NB) aggressiveness. Recently, we demonstrated that the expression of MYCN, a poor prognosis marker in NB, inversely correlates with that of activating ligands. This indicates that MYCN expression level can predict the susceptibility of NB cells to NK cell-mediated immunotherapy and that its downregulation can be exploited as a novel therapeutic strategy to induce the expression of activating ligands. Here we evaluated the effect of the BET-bromodomain inhibitor JQ1 on the expression of ligands for NK cell-activating receptors in NB cell lines. Although downmodulating MYCN, JQ1 impaired the expression of ligands for NK cell-activating receptors, rendering NB cell lines more resistant to NK cell-mediated killing. The downregulation of activating ligands was due to JQ1-mediated impaired functions of both c-MYC and p53, two transcription factors known to regulate the expression of ULBP1-3 ligands for NKG2D activating receptor. Moreover JQ1 strongly downregulated the levels of ROS, a stress-induced signaling event associated with the induction of ligands for NK cell-activating receptors. These results suggest that the use of JQ1 should be discourage in combination with NK cell-based immunotherapy in a perspective chemotherapeutic treatment of NB. Thus, further investigations, exploiting molecular strategies aimed to boost the NK cell-mediated killing of NB cells, are warranted.

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Section: Discussionmentioning

confidence: 99%

The BET-bromodomain inhibitor JQ1 renders neuroblastoma cells more resistant to NK cell-mediated recognition and killing by downregulating ligands for NKG2D and DNAM-1 receptors

et al. 2019

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“…The improvement of clinical efficacy of immunotherapy strategies is a central goal of translational and clinical research in immunooncology. In recent years, several factors have been shown to influence the immune response during ICI treatment ( 80 - 83 ). In this context, the human microbiota seems to be an important modulator of the immune system response in different physiopathological conditions, including cancer development and response to anti-cancer treatment ( 84 ).…”

Section: Host Microbiota and Response To Immunotherapymentioning

confidence: 99%

Cutaneous melanoma and the immunotherapy revolution (Review)

et al. 2020

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In a relatively short period of time, treatment strategies for metastatic melanoma have radically changed leading to an unprecedented improvement in patient survival. In this period, immunotherapy options have evolved from cytokine-based approaches to antibody-mediated inhibition of immune checkpoints, cancer vaccines and pharmacological modulation of the melanoma microenvironment. Combination of immunotherapy strategies and the association of immune checkpoint inhibitors (ICIs) with BRAF V600 targeted therapy show encouraging results. The future of drug development in this field is promising. The comprehension of primary and acquired resistance mechanisms to ICIs and the dissection of melanoma immunobiology will be instrumental for the development of new treatment strategies and to improve clinical trial design. Moreover, biomarker discovery will help patient stratification and management during immunotherapy treatment. In this review, we summarize landmark clinical trials of immune checkpoint inhibitors in advanced melanoma and discuss the rational for immunotherapy combinations. Immunotherapy approaches at early stage of clinical development and recent advances in melanoma immunotherapy biomarker development are also discussed.

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“…Similar to its glucose-lowering effect, the immunomodulatory effect of metformin mainly depends on the activation of AMP-activated protein kinase (AMPK) ( 32 – 34 ) ( Figure 2 ). In brief, metformin directly inhibits respiratory-chain complex 1 of the mitochondrial electron transport chain, resulting in a reduction in ATP synthesis and thereby an increase in the AMP/ATP or ADP/ATP ratio, which consequentially activates AMPK through the binding of either AMP or ADP.…”

Section: Metformin Inhibits Inflammatory Responses and Alleviates Acumentioning

confidence: 99%

Immunomodulatory and Antiviral Activity of Metformin and Its Potential Implications in Treating Coronavirus Disease 2019 and Lung Injury

et al. 2020

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The pandemic of coronavirus disease 2019 (COVID-19), a disease which causes severe lung injury and multiple organ damage, presents an urgent need for new drugs. The case severity and fatality of COVID-19 are associated with excessive inflammation, namely, a cytokine storm. Metformin, a widely used drug to treat type 2 diabetes (T2D) mellitus and metabolic syndrome, has immunomodulatory activity that reduces the production of proinflammatory cytokines using macrophages and causes the formation of neutrophil extracellular traps (NETs). Metformin also inhibits the cytokine production of pathogenic Th1 and Th17 cells. Importantly, treatment with metformin alleviates various lung injuries in preclinical animal models. In addition, a recent proteomic study revealed that metformin has the potential to directly inhibit SARS-CoV-2 infection. Furthermore, retrospective clinical studies have revealed that metformin treatment reduces the mortality of T2D with COVID-19. Therefore, metformin has the potential to be repurposed to treat patients with COVID-19 at risk of developing severe illness. This review summarizes the immune pathogenesis of SARS-CoV-2 and addresses the effects of metformin on inhibiting cytokine storms and preventing SARS-CoV-2 infection, as well as its side effects.

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Immunomodulatory Effects of Drugs for Effective Cancer Immunotherapy

Cited by 32 publications

References 69 publications

The BET-bromodomain inhibitor JQ1 renders neuroblastoma cells more resistant to NK cell-mediated recognition and killing by downregulating ligands for NKG2D and DNAM-1 receptors

The BET-bromodomain inhibitor JQ1 renders neuroblastoma cells more resistant to NK cell-mediated recognition and killing by downregulating ligands for NKG2D and DNAM-1 receptors

Cutaneous melanoma and the immunotherapy revolution (Review)

Immunomodulatory and Antiviral Activity of Metformin and Its Potential Implications in Treating Coronavirus Disease 2019 and Lung Injury

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