Metformin as an archetype immuno-metabolic adjuvant for cancer immunotherapy

Verdura, Sara; Cuyàs, Elisabet; Martín-Castillo, Begoña; Menendez, Javier A.

doi:10.1080/2162402x.2019.1633235

Cited by 81 publications

(80 citation statements)

References 118 publications

(119 reference statements)

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“…The recently discovered ability of the mitochondrial I inhibitor metformin to target PD-L1 in cancer cells [67] provides support to the notion that the cancer cell-auto-nomous metabolic status can shape the composition of immune checkpoints in cancer cells. The activated form of AMPK generated in response to the metabolic crisis induced by metformin has been found to directly phosphorylate PD-L1 in a manner that promotes its abnormal glycosylation, resulting in ER accumulation and ER-associated protein degradation [39,67]. We here characterized the unforeseen ability of RSV to disrupt Nlinked glycosylation of PD-L1 and consequently reduce PD-L1 maturation and, ultimately, hamper its cancer cell surface-associated expression.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, the inhibitory nature of the metabolic interplay between tumor and immune cells in the TME supports its suitability as a target to overcome the immune escape of cancer cells and circumvent immunotherapy resistance. Accordingly, various combinations of immunotherapies with metabolic agents aimed to rewire T-cell fitness -by suppressing the immunosuppressive metabolic traits within the TME -are being tested in clinical trials [36][37][38][39]. Nonetheless, the appraisal of cancer cellautonomous metabolic reprogramming as a bona fide driver of immune checkpoint signaling in tumor cells is a largely neglected area in cancer immunometabolism.…”

Section: Introductionmentioning

confidence: 99%

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Resveratrol targets PD-L1 glycosylation and dimerization to enhance antitumor T-cell immunity

Verdura

Cuyàs

Cortada

et al. 2020

Aging

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114

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New strategies to block the immune evasion activity of programmed death ligand-1 (PD-L1) are urgently needed. When exploring the PD-L1-targeted effects of mechanistically diverse metabolism-targeting drugs, exposure to the dietary polyphenol resveratrol (RSV) revealed its differential capacity to generate a distinct PD-L1 electrophoretic migration pattern. Using biochemical assays, computer-aided docking/molecular dynamics simulations, and fluorescence microscopy, we found that RSV can operate as a direct inhibitor of glyco-PD-L1-processing enzymes (α-glucosidase/α-mannosidase) that modulate N-linked glycan decoration of PD-L1, thereby promoting the endoplasmic reticulum retention of a mannose-rich, abnormally glycosylated form of PD-L1. RSV was also predicted to interact with the inner surface of PD-L1 involved in the interaction with PD-1, almost perfectly occupying the target space of the small compound BMS-202 that binds to and induces dimerization of PD-L1. The ability of RSV to directly target PD-L1 interferes with its stability and trafficking, ultimately impeding its targeting to the cancer cell plasma membrane. Impedance-based real-time cell analysis (xCELLigence) showed that cytotoxic T-lymphocyte activity was notably exacerbated when cancer cells were previously exposed to RSV. This unforeseen immunomodulating mechanism of RSV might illuminate new approaches to restore T-cell function by targeting the PD-1/PD-L1 immunologic checkpoint with natural polyphenols.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Resveratrol targets PD-L1 glycosylation and dimerization to enhance antitumor T-cell immunity

Verdura

Cuyàs

Cortada

et al. 2020

Aging

Self Cite

114

View full text Add to dashboard Cite

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“…SCORTEN has been deemed an accurate scoring system for estimation of mortality among TEN patients treated in burn centers [17]. Metformin has been noted to downregulate PD-1 expression in tumor cells and showed increased efficacy of immunotherapy [18]. In our patient during re-challenge, she developed a recurrence of rash possibly due to weight-based dosing of immunotherapy.…”

Section: Discussionmentioning

confidence: 73%

Immune-Mediated Toxic Epidermal Necrolysis

Keerty

Koverzhenko

Belinc

et al. 2020

Cureus

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The treatment of melanoma has advanced over time with the latest modalities being immune checkpoint blockade by programmed death receptor 1 and cytotoxic T-lymphocyte-associated antigen 4 inhibitors. Programmed death receptor 1 inhibitors have been noted to cause multisystem adverse reactions. The dermatological adverse events can range from pruritus to severe toxic epidermal necrolysis. We report a fatal case of toxic epidermal necrolysis secondary to nivolumab therapy. Checkpoint inhibitors are becoming the standard treatment option in many malignancies. Their safety profile is still evolving as more cases are being reported. Many individuals who are immunocompromised or undergoing concomitant treatment with combination therapy could develop significant overlapping toxicities. Physicians must be vigilant for dermatological complications that lead to opportunistic infections and sepsis.

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“…Similar to these results, Verdure et al . mentioned that metformin improves cytotoxicity of CD8+ T-cells by reducing the membrane-bound PD-L1 level increased by TNF-γ treatment ( 68 ). Consistently, Han et al .…”

Section: The Effect Of Metformin On Anti-tumor Immunitymentioning

confidence: 99%

A new aspect of an old friend: the beneficial effect of metformin on anti-tumor immunity

et al. 2020

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T-cell-based cancer immunotherapies, such as immune checkpoint blockers (ICBs) and chimeric antigen receptor (CAR)-T-cells, have significant anti-tumor effects against certain types of cancer, providing a new paradigm for cancer treatment. However, the activity of tumor infiltrating T-cells (TILs) can be effectively neutralized in the tumor microenvironment (TME) of most solid tumors, rich in various immunosuppressive factors and cells. Therefore, to improve the clinical outcomes of established T-cell-based immunotherapy, adjuvants that can comprehensively relieve multiple immunosuppressive mechanisms of TME are needed. In this regard, recent studies have revealed that metformin has several beneficial effects on anti-tumor immunity. In this mini-review, we understand the immunosuppressive properties of TME and how metformin comprehensively enhances anti-tumor immunity. Finally, we will discuss this old friend’s potential as an adjuvant for cancer immunotherapy.

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Metformin as an archetype immuno-metabolic adjuvant for cancer immunotherapy

Cited by 81 publications

References 118 publications

Resveratrol targets PD-L1 glycosylation and dimerization to enhance antitumor T-cell immunity

Resveratrol targets PD-L1 glycosylation and dimerization to enhance antitumor T-cell immunity

Immune-Mediated Toxic Epidermal Necrolysis

A new aspect of an old friend: the beneficial effect of metformin on anti-tumor immunity

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