Clinical Outcomes in Non-Small-Cell Lung Cancer Patients Receiving Concurrent Metformin and Immune Checkpoint Inhibitors

Afzal, Muhammad Zubair; Dragnev, Konstantin H.; Sarwar, Tayyaba; Shirai, Keisuke

doi:10.2217/lmt-2018-0016

Cited by 69 publications

(57 citation statements)

References 62 publications

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“…The present evidence partly supports the use of metformin in combination with ICIs for improving the treatment of several cancers. This therapeutic schedule is also associated with a substantial risk of adverse effects ( 1 , 11 ). Various approaches are underway to expand the benefits and improve the efficacy of these ICIs.…”

Section: Discussionmentioning

confidence: 99%

“…Based on the promoting effects of metformin on anti-PD-1/PD-L1 therapy in preclinical studies, more scientists are concentrating on the antitumor effects of metformin in combination with ICIs (as summarized in Table 1 ). Several studies observed favorable treatment outcomes (objective response rate, disease control rate, median progression-free survival, and median overall survival) in patients who received metformin in combination with ICIs without reaching a statistically significant trend ( 1 , 11 , 37 ). The subgroup analysis found a statistically significant association between metformin use and OS in obese patients with a BMI >25 kg/m 2 ; the strength of the association was higher in patients with a BMI >30 kg/m 2 ( 31 ).…”

Section: Metformin Influences the Antitumor Efficiency Of Icismentioning

confidence: 99%

“…Over the past decade, cancer has emerged as one of the most important threats to public health because of its high morbidity and mortality ( 1 ). Although there is a long way to go before cancer is completely conquered, the pace of scientists’ fight has never slowed down.…”

Section: Introductionmentioning

confidence: 99%

“…A previous study found that metformin combined with anti-PD-1 therapy had a potential benefit in mouse models, as the metformin-induced reduction of the tumor hypoxia enhanced the efficacy of PD-1 blockade ( 10 ). Recently, more attention has been given to the T cell-mediated antitumor response of metformin in the immunosuppressive process of cancer therapy ( 1 , 11 ). Extensive research has suggested that metformin has the potential to enhance antitumor immune responses in different types of cancers.…”

Section: Introductionmentioning

confidence: 99%

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Pleiotropic Effects of Metformin on the Antitumor Efficiency of Immune Checkpoint Inhibitors

et al. 2021

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Cancer is an important threat to public health because of its high morbidity and mortality. In recent decades, immune checkpoint inhibitors (ICIs) have ushered a new therapeutic era in clinical oncology. The rapid development of immune checkpoint therapy is due to its inspiring clinical efficacy in a group of cancer types. Metformin, an effective agent for the management of type 2 diabetes mellitus (T2DM), has shown beneficial effects on cancer prevention and cancer treatment. Emerging studies have suggested that metformin in combination with ICI treatment could improve the anticancer effects of ICIs. Hence, we conducted a review to summarize the effects of metformin on ICI therapy. We also review the pleiotropic mechanisms of metformin combined with ICIs in cancer therapy, including its direct and indirect effects on the host immune system.

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Section: Discussionmentioning

confidence: 99%

Section: Metformin Influences the Antitumor Efficiency Of Icismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pleiotropic Effects of Metformin on the Antitumor Efficiency of Immune Checkpoint Inhibitors

et al. 2021

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“…Other compounds that can modulate PD-L1 expression could provide alternatives to antibodies with different pharmacological properties and toxicity profiles, which may be used in combinational therapy. For example, metformin induces degradation of PD-L1 through endoplasmic reticulum-associated (16) or other signaling pathways (17), and was shown to improve overall response and disease control rate in combination with checkpoint inhibitors in small clinical trials in NSCLC (18) and melanoma (19). Many natural compounds (e.g.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of GFAT1 in lung cancer cells destabilizes PD-L1 protein and improves immune response

Chen

Saxton

2020

Preprint

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Immunotherapy using checkpoint blockers (antibodies) has been a major advance in recent years in the management of various types of solid cancers including lung cancer. One target of checkpoint blockers is programmed death ligand 1 (PD-L1) expressed by cancer cells, which engages programmed death 1 (PD-1) on T cells and Natural Killer (NK) cells resulting in suppression of their activation and cancer-killing function, respectively. Apart from antibodies, other clinically relevant agents that can inhibit PD-L1 are limited. PD-L1 protein stability depends on its glycosylation. Here we show that L-glutamine:D-fructose amidotransferase 1 (GFAT1) a rate-limiting enzyme of the hexosamine biosynthesis pathway (HBP) which produces uridine diphosphate-N-acetyl-β-glucosamine (UDP-GlcNAc), a precursor for glycosylation, is required for the stability of PD-L1 protein. Inhibition of GFAT1 activity markedly reduced interferon γ (IFNγ)-induced PD-L1 levels in various lung cancer cell lines. GFAT1 inhibition suppressed glycosylation of PD-L1 and accelerated its proteasomal degradation. Importantly, inhibition of GFAT1 in IFNγ-treated cancer cells enhanced the activation of T cells and the cancer-killing activity of NK cells. These findings support using GFAT1 inhibitors to manipulate PD-L1 protein level that could augment the efficacy of immunotherapy for lung cancer.

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Metabolic regulation in the immune response to cancer

et al. 2021

Cancer Communications

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Metabolic reprogramming in tumor‐immune interactions is emerging as a key factor affecting pro‐inflammatory carcinogenic effects and anticancer immune responses. Therefore, dysregulated metabolites and their regulators affect both cancer progression and therapeutic response. Here, we describe the molecular mechanisms through which microenvironmental, systemic, and microbial metabolites potentially influence the host immune response to mediate malignant progression and therapeutic intervention. We summarized the primary interplaying factors that constitute metabolism, immunological reactions, and cancer with a focus on mechanistic aspects. Finally, we discussed the possibility of metabolic interventions at multiple levels to enhance the efficacy of immunotherapeutic and conventional approaches for future anticancer treatments.

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Clinical Outcomes in Non-Small-Cell Lung Cancer Patients Receiving Concurrent Metformin and Immune Checkpoint Inhibitors

Cited by 69 publications

References 62 publications

Pleiotropic Effects of Metformin on the Antitumor Efficiency of Immune Checkpoint Inhibitors

Pleiotropic Effects of Metformin on the Antitumor Efficiency of Immune Checkpoint Inhibitors

Inhibition of GFAT1 in lung cancer cells destabilizes PD-L1 protein and improves immune response

Metabolic regulation in the immune response to cancer

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