Overcoming acquired resistance to PD-1 inhibitor with the addition of metformin in small cell lung cancer (SCLC)

Kim, Yeseul; Vagia, Elena; Viveiros, Pedro Hermida de; Kang, Cyra Y.; Lee, Ju Young; Gim, Gahyun; Cho, Sukjoo; Choi, Horyun; Kim, Leeseul; Park, In-Ae; Choi, Jaeyoun; Chae, Young Kwang

doi:10.1007/s00262-020-02703-8

Cited by 33 publications

(28 citation statements)

References 14 publications

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“…Metformin was reported to impede hypoxia-mediated immunosuppression by inhibiting mitochondrial respiratory chain complex I and inducing O 2 -dependent degradation of HIF-1α in the hepatoma cell line Huh7 (Figure 7) [109]. Furthermore, Kim's study suggested that patients with small-cell lung cancer (SCLC) had a prolonged durable response to nivolumab (FDA-approved third-line immunotherapy to SCLC) after metformin treatment to alter O 2 consumption by nivolumab-resistant SCLC cells because the hypoxic microenvironment confers immunoresistance to cancer cells [110,111].…”

Section: Hypoxiamentioning

confidence: 99%

New Insight into the Effects of Metformin on Diabetic Retinopathy, Aging and Cancer: Nonapoptotic Cell Death, Immunosuppression, and Effects beyond the AMPK Pathway

Hsu

Cheng

Mgbeahuruike

et al. 2021

IJMS

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Under metabolic stress conditions such as hypoxia and glucose deprivation, an increase in the AMP:ATP ratio activates the AMP-activated protein kinase (AMPK) pathway, resulting in the modulation of cellular metabolism. Metformin, which is widely prescribed for type 2 diabetes mellitus (T2DM) patients, regulates blood sugar by inhibiting hepatic gluconeogenesis and promoting insulin sensitivity to facilitate glucose uptake by cells. At the molecular level, the most well-known mechanism of metformin-mediated cytoprotection is AMPK pathway activation, which modulates metabolism and protects cells from degradation or pathogenic changes, such as those related to aging and diabetic retinopathy (DR). Recently, it has been revealed that metformin acts via AMPK- and non-AMPK-mediated pathways to exert effects beyond those related to diabetes treatment that might prevent aging and ameliorate DR. This review focuses on new insights into the anticancer effects of metformin and its potential modulation of several novel types of nonapoptotic cell death, including ferroptosis, pyroptosis, and necroptosis. In addition, the antimetastatic and immunosuppressive effects of metformin and its hypothesized mechanism are also discussed, highlighting promising cancer prevention strategies for the future.

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Section: Hypoxiamentioning

confidence: 99%

New Insight into the Effects of Metformin on Diabetic Retinopathy, Aging and Cancer: Nonapoptotic Cell Death, Immunosuppression, and Effects beyond the AMPK Pathway

Hsu

Cheng

Mgbeahuruike

et al. 2021

IJMS

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“…To revert the hypoxic environment in addition to targeting the vasculature, different nanoparticles containing MnO 2 have been utilized in murine models with the double function to transport the therapeutic cargo to the tumor and then to decompose in situ and release oxygen to revert local hypoxia and thus to further promote response to immunotherapy [ 115 , 116 ]. Similarly, the antidiabetic drug metformin by inhibiting the mitochondrial complex I and thus reducing oxygen consumption via the mitochondria has provided encouraging results in reverting tumor hypoxia and in improving immune cell functions both in mice and in humans [ 117 , 118 ]. Targeted therapy or blocking antibodies have also being utilized to directly inhibit the suppressive cytokine TGF-β [ 119 ] or to reduce adenosine production by suppressive immune cells as well as tumor cells via CD73, CD39, or CD38 [ 120 , 121 ].…”

Section: Mechanism Of Tumor Resistancementioning

confidence: 99%

Immune Therapy Resistance and Immune Escape of Tumors

Seliger

Massa

2021

Cancers

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Immune therapy approaches such as checkpoint inhibitors or adoptive cell therapy represent promising therapeutic options for cancer patients, but their efficacy is still limited, since patients frequently develop innate or acquired resistances to these therapies. Thus, one major goal is to increase the efficiency of immunotherapies by overcoming tumor-induced immune suppression, which then allows for immune-mediated tumor clearance. Innate resistance to immunotherapies could be caused by a low immunogenicity of the tumor itself as well as an immune suppressive microenvironment composed of cellular, physical, or soluble factors leading to escape from immune surveillance and disease progression. So far, a number of strategies causing resistance to immunotherapy have been described in various clinical trials, which broadly overlap with the immunoediting processes of cancers. This review summarizes the novel insights in the development of resistances to immune therapy as well as different approaches that could be employed to overcome them.

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“…A preclinical study showed that the anticancer effect of CD8+ T tumor-infiltrating lymphocytes (CD8TILs) is suppressed by the interaction between ICIs such as PD-1 and CTLA-4 expressed on CD8TILs and their ligands expressed on cancer cells; this process is referred to as immune exhaustion. CD8TILs are the target of metformin, which can counter this suppressed state and block immune exhaustion within tumor tissues via AMPK-mTOR signaling ( 57 ). Thus, the activity of CD8TILs in eliminating cancer cells in tumor tissues is enhanced ( 55 ).…”

Section: Possible Mechanisms Of Metformin In Enhancing the Antitumor mentioning

confidence: 99%

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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Overcoming acquired resistance to PD-1 inhibitor with the addition of metformin in small cell lung cancer (SCLC)

Cited by 33 publications

References 14 publications

New Insight into the Effects of Metformin on Diabetic Retinopathy, Aging and Cancer: Nonapoptotic Cell Death, Immunosuppression, and Effects beyond the AMPK Pathway

New Insight into the Effects of Metformin on Diabetic Retinopathy, Aging and Cancer: Nonapoptotic Cell Death, Immunosuppression, and Effects beyond the AMPK Pathway

Immune Therapy Resistance and Immune Escape of Tumors

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

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