Metformin keeps CD8+ T cells active and moving in NASH-HCC immunotherapy

Lujambio, Amaia; Sarobe, Pablo

doi:10.1016/j.jhep.2022.05.038

Cited by 8 publications

(9 citation statements)

References 12 publications

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“…In parallel, the contribution of innate immunity inflammatory cells such as TAMs [ 121 ] and TANs [ 122 ] and of signaling systems such as the NOD-like receptor family, pyrin domain-containing protein 3 (NLRP3) inflammasome [ 123 ] has been increasingly recognized for their contributions in the progression of HCC. Recent evidence has implicated metformin in the regulation of HCC immune TME [ 124 ]. In addition to the induction of apoptosis, which was analyzed above, metformin attenuates HCC cell proliferation, activating proptosis.…”

Section: Metformin As An Immunotherapy Enhancermentioning

confidence: 99%

“…They found that metformin reprogramed CD8+ T cells and restored their motility and sensitivity to immunotherapies. Finally, they demonstrated the translational potential of metformin, as it synergized with anti-PD-1 monotherapy or with the combination immunotherapy of anti-VEGFR2 and anti-PD-L1 [ 124 , 128 ]. For additional study into the T-cell motility dynamics, an extensive review has been conducted elsewhere [ 129 ].…”

Section: Metformin As An Immunotherapy Enhancermentioning

confidence: 99%

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The Emerging Role of Metformin in the Treatment of Hepatocellular Carcinoma: Is There Any Value in Repurposing Metformin for HCC Immunotherapy?

Papadakos

Ferraro

Carbone

et al. 2023

Cancers

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Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. There has been significant progress in understanding the risk factors and epidemiology of HCC during the last few decades, resulting in efficient preventative, diagnostic and treatment strategies. Type 2 diabetes mellitus (T2DM) has been demonstrated to be a major risk factor for developing HCC. Metformin is a widely used hypoglycemic agent for patients with T2DM and has been shown to play a potentially beneficial role in improving the survival of patients with HCC. Experimental and clinical studies evaluating the outcomes of metformin as an antineoplastic drug in the setting of HCC were reviewed. Pre-clinical evidence suggests that metformin may enhance the antitumor effects of immune checkpoint inhibitors (ICIs) and reverse the effector T cells’ exhaustion. However, there is still limited clinical evidence regarding the efficacy of metformin in combination with ICIs for the treatment of HCC. We appraised and analyzed in vitro and animal studies that aimed to elucidate the mechanisms of action of metformin, as well as clinical studies that assessed its impact on the survival of HCC patients.

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Section: Metformin As An Immunotherapy Enhancermentioning

confidence: 99%

Section: Metformin As An Immunotherapy Enhancermentioning

confidence: 99%

The Emerging Role of Metformin in the Treatment of Hepatocellular Carcinoma: Is There Any Value in Repurposing Metformin for HCC Immunotherapy?

Papadakos

Ferraro

Carbone

et al. 2023

Cancers

View full text Add to dashboard Cite

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“…Meanwhile, it has been found that patients with NASH-driven HCC are less sensitive to anti-PD1 or anti-PDL1 treatment in comparison to patients with other etiologies ( 139 ). Impaired response to immunotherapy in NASH-driven HCC is associated with reduced motility and abnormal metabolic functions of CD8 + T cells rather than infiltration of CD8 + T cells and concentration of effector CD8 + T cells in tumor tissue ( 147 , 148 ). Further researches need to be done to explore the reason why NASH-induced HCC is less sensitive to immunotherapy, which can not only broaden our horizons in the mechanism by which NASH promotes HCC but also help us to find targeted population of immunotherapy in HCC and investigate the feasibility of combined therapy in NASH-induced HCC.…”

Section: Cd8 + T Cells In Nash-induced Hccmentioning

confidence: 99%

Crucial role of T cells in NAFLD-related disease: A review and prospect

et al. 2022

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Nonalcoholic fatty liver disease (NAFLD) includes a series of hepatic manifestations, starting with liver steatosis and potentially evolving towards nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis or even hepatocellular carcinoma (HCC). Its incidence is increasing worldwide. Several factors including metabolic dysfunction, oxidative stress, lipotoxicity contribute to the liver inflammation. Several immune cell-mediated inflammatory processes are involved in NAFLD in which T cells play a crucial part in the progression of the disease. In this review, we focus on the role of different subsets of both conventional and unconventional T cells in pathogenesis of NAFLD. Factors regarding inflammation and potential therapeutic approaches targeting immune cells in NASH are also discussed.

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“…It dampens cytokine production in macrophages and lymphocytes [8,9] and inhibits the NF-κB signaling pathway [10]. Moreover, metformin promotes the proliferation of regulatory T cells, which are crucial for tempering overactive immune responses [11,12]. Despite these known effects, the specific impact of metformin on neutrophilic inflammatory behavior has not been fully explored.…”

Section: Introductionmentioning

confidence: 99%

Metformin Attenuates Neutrophil Recruitment through the H3K18 Lactylation/Reactive Oxygen Species Pathway in Zebrafish

Zhou,

Ding,

et al. 2024

Antioxidants

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Beyond its well-established role in diabetes management, metformin has gained attention as a promising therapeutic for inflammation-related diseases, largely due to its antioxidant capabilities. However, the mechanistic underpinnings of this effect remain elusive. Using in vivo zebrafish models of inflammation, we explored the impact of metformin on neutrophil recruitment and the underlying mechanisms involved. Our data indicate that metformin reduces histone (H3K18) lactylation, leading to the decreased production of reactive oxygen species (ROS) and a muted neutrophil response to both caudal fin injury and otic vesicle inflammation. To investigate the precise mechanisms through which metformin modulates neutrophil migration via ROS and H3K18 lactylation, we meticulously established the correlation between metformin-induced suppression of H3K18 lactylation and ROS levels. Through supplementary experiments involving the restoration of lactate and ROS, our findings demonstrated that elevated levels of both lactate and ROS significantly promoted the inflammatory response in zebrafish. Collectively, our study illuminates previously unexplored avenues of metformin’s antioxidant and anti-inflammatory actions through the downregulation of H3K18 lactylation and ROS production, highlighting the crucial role of epigenetic regulation in inflammation and pointing to metformin’s potential in treating inflammation-associated conditions.

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Metformin keeps CD8+ T cells active and moving in NASH-HCC immunotherapy

Cited by 8 publications

References 12 publications

The Emerging Role of Metformin in the Treatment of Hepatocellular Carcinoma: Is There Any Value in Repurposing Metformin for HCC Immunotherapy?

The Emerging Role of Metformin in the Treatment of Hepatocellular Carcinoma: Is There Any Value in Repurposing Metformin for HCC Immunotherapy?

Crucial role of T cells in NAFLD-related disease: A review and prospect

Metformin Attenuates Neutrophil Recruitment through the H3K18 Lactylation/Reactive Oxygen Species Pathway in Zebrafish

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