Inactivation of AMPK Leads to Attenuation of Antigen Presentation and Immune Evasion in Lung Adenocarcinoma

Gao, Yajing; Päivinen, Pekka; Tripathi, Sushil; Domènech-Moreno, Eva; Wong, Iris P.L.; Vaahtomeri, Kari; Nagaraj, Ashwini S.; Talwelkar, Sarang S.; Foretz, Marc; Verschuren, Emmy W.; Viollet, Benoı̂t; Yan, Yan; Mäkelä, Tomi P.

doi:10.1158/1078-0432.ccr-21-2049

Cited by 14 publications

(10 citation statements)

References 45 publications

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“…AMPK can also epigenetically modulate gene transcription by phosphorylating demethylase TET2 and/or methyltransferase EZH2 33,34 . Moreover, a recent study has found that AMPK can reduce immune evasion by promoting antigen presentation 35 . On the other hand, AMPK is essential for KRAS‐driven tumorigenesis and cancer cell survival 36 ; in addition, it is crucial for the resistance of energy stress–induced oxidative damage 37 .…”

Section: Discussionmentioning

confidence: 99%

“… 33 , 34 Moreover, a recent study has found that AMPK can reduce immune evasion by promoting antigen presentation. 35 On the other hand, AMPK is essential for KRAS‐driven tumorigenesis and cancer cell survival 36 ; in addition, it is crucial for the resistance of energy stress–induced oxidative damage. 37 The regulation of autophagy by AMPK can also promote the survival of tumor cells in some cases.…”

Section: Discussionmentioning

confidence: 99%

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A subset of VEGFR‐TKIs activates AMPK in LKB1‐mutant lung cancer

et al. 2022

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The mutation of tumor suppressor gene liver kinase B1 (LKB1) has a prevalence of about 20% in non–small cell lung cancer (NSCLC). LKB1‐mutant lung cancer is characterized by enhanced aggressiveness and immune escape and is associated with poor prognosis. Therefore, it is urgent to develop effective therapeutic methods for LKB1‐mutant NSCLC. Recently, apatinib, a VEGFR‐TKI, was found to significantly improve the outcome of LKB1‐mutant NSCLC, but the mechanism is not completely clear. In this study, AMP‐activated protein kinase (AMPK), the crucial downstream kinase of LKB1 was excavated as the potential target of apatinib. Biochemical experiments verified that apatinib is a direct AMPK activator. Moreover, clinically available VEGFR‐TKIs were found to regulate AMPK differently: Apatinib and anlotinib can directly activate AMPK, while axitinib and sunitinib can directly inhibit AMPK. Activation of AMPK by apatinib leads to the phosphorylation of acetyl‐CoA carboxylase (ACC) and inhibition of de novo fatty acid synthesis (FAsyn), which is upregulated in LKB1‐null cancers. Moreover, the killing effect of apatinib was obviously enhanced under delipidated condition, and the combination of exogenous FA restriction with apatinib treatment can be a promising method for treating LKB1‐mutant NSCLC. This study discovered AMPK as an important off‐target of apatinib and elucidated different effects of this cluster of VEGFR‐TKIs on AMPK. This finding can be the basis for the accurate and combined application of these drugs in clinic and highlights that the subset of VEGFR‐TKIs including apatinib and anlotinib are potentially valuable in the treatment of LKB1‐mutant NSCLC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A subset of VEGFR‐TKIs activates AMPK in LKB1‐mutant lung cancer

et al. 2022

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“…AMPKα-1-mediated inhibition of mTORC1 activity in cytotoxic T lymphocytes (CTLs) is required for CD8 + T-cell memory ( 140 ). Previous studies have revealed that inactivation of both AMPK α 1 and α 2 coupled with Kirsten rat sarcoma virus (KRAS) activation promotes tumorigenesis and decreases the infiltration of CD8 + /CD4 + T cells ( 141 ). Braverman et al., have reported that increasing AMPK activity orchestrates oxidative metabolism, proliferation, and in vitro recovery of human CD4 + T cells.…”

Section: Molecular Crosstalk Of Ampk Drives Anti-tumor Immune Respons...mentioning

confidence: 99%

“…Tumor-associated macrophages (TAMs) are present in abundance across various types of malignant tumors and promote tumor angiogenesis, extravasation and metastasis ( 144 ).Macrophages are responsible for driving anti-tumor immunity via phagocytosis and antigen presentation. Macrophages exist in two distinct phenotypes namely, the ‘classically’ activated, tumoricidal phenotype, M1φ, and the ‘alternatively’ activated pro-tumorigenic phenotype, M2φ ( 145 ).Some documented results indicate that AMPK inhibition leads to an up-surge in LPS-induced macrophage inflammatory function ( 141 ). Previous reports also state that AMPK prevents the polarization of monocyte-derived macrophages towards the M2φ subtype ( 146 ).Chiang et al., reported that metformin-mediated AMPK activation suppresses the skewing of macrophage towards M2φ subtype in breast cancer cells ( 147 ).…”

Section: Molecular Crosstalk Of Ampk Drives Anti-tumor Immune Respons...mentioning

confidence: 99%

The role of AMPK in cancer metabolism and its impact on the immunomodulation of the tumor microenvironment

et al. 2023

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Adenosine monophosphate-activated protein kinase (AMPK) is a key metabolic sensor that is pivotal for the maintenance of cellular energy homeostasis. AMPK contributes to diverse metabolic and physiological effects besides its fundamental role in glucose and lipid metabolism. Aberrancy in AMPK signaling is one of the determining factors which lead to the development of chronic diseases such as obesity, inflammation, diabetes, and cancer. The activation of AMPK and its downstream signaling cascades orchestrate dynamic changes in the tumor cellular bioenergetics. It is well documented that AMPK possesses a suppressor role in the context of tumor development and progression by modulating the inflammatory and metabolic pathways. In addition, AMPK plays a central role in potentiating the phenotypic and functional reprogramming of various classes of immune cells which reside in the tumor microenvironment (TME). Furthermore, AMPK-mediated inflammatory responses facilitate the recruitment of certain types of immune cells to the TME, which impedes the development, progression, and metastasis of cancer. Thus, AMPK appears to play an important role in the regulation of anti-tumor immune response by regulating the metabolic plasticity of various immune cells. AMPK effectuates the metabolic modulation of anti-tumor immunity via nutrient regulation in the TME and by virtue of its molecular crosstalk with major immune checkpoints. Several studies including that from our lab emphasize on the role of AMPK in regulating the anticancer effects of several phytochemicals, which are potential anticancer drug candidates. The scope of this review encompasses the significance of the AMPK signaling in cancer metabolism and its influence on the key drivers of immune responses within the TME, with a special emphasis on the potential use of phytochemicals to target AMPK and combat cancer by modulating the tumor metabolism.

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“…A prospective study about cytokine profiles in NSCLC patients receiving ICI treatment in the second line revealed that patients with elevated expression of IFN-γ significantly benefit from PD-1 blockers ( 61 ). Moreover, attenuated antigen presentation was also found in NSCLC with compromised LKB1 and AMPK activity ( 62 ). Low expression of KAT2B concurrent with a higher frequency of somatic genes mutation was associated with lower response efficacy to ICIs in NSCLC patients, while KAT2B was linked to IFN-γ regulation, antigen processing, and presentation ( 63 ).…”

Section: Mechanisms Of Immunotherapy Resistance In Nsclcmentioning

confidence: 99%

Immunotherapy resistance in non-small-cell lung cancer: From mechanism to clinical strategies

Zhou

Yang

2023

Front. Immunol.

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The high primary resistance incidence and unavoidable secondary resistance are the major clinical obstacle to lasting long-term benefits in Non-small-cell lung cancer (NSCLC) patients treated with immunotherapy. The mechanisms of immunotherapy resistance in NSCLC are complex, mainly involving tumor cells and tumor microenvironment (TME) infiltrating immune cells, including TAMs, B cells, NK cells, and T cells. The selection of clinical strategies for NSCLC progression after immunotherapy resistance should depend on the progressive mode. The progression pattern of NSCLC patients after immunotherapy resistance can be divided into oligo-progression and systemic/multiple progression, which should be considered for further treatment selection. In the future, it needs to explore how to optimize the combined therapy and explore strategies to reprogram infiltrating immune cells under various genetic backgrounds of tumor cells and timely reshape TME during antitumor treatments.

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Inactivation of AMPK Leads to Attenuation of Antigen Presentation and Immune Evasion in Lung Adenocarcinoma

Cited by 14 publications

References 45 publications

A subset of VEGFR‐TKIs activates AMPK in LKB1‐mutant lung cancer

A subset of VEGFR‐TKIs activates AMPK in LKB1‐mutant lung cancer

The role of AMPK in cancer metabolism and its impact on the immunomodulation of the tumor microenvironment

Immunotherapy resistance in non-small-cell lung cancer: From mechanism to clinical strategies

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