Nature Metabolism Yang Weiwei/Zhao Yun/Yao Feng Reveal a New Mechanism of Pyruvate Dehydrogenase in Lung Cancer Immune Escape

iNature tumor cells utilize multiple strategies to evade the immune system, but the underlying metabolic mechanisms remain poorly understood
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The pyruvate dehydrogenase (PDH) complex converts pyruvate to acetyl-CoA in mitochondria, thereby linking glycolysis to the abundant carboxylic acid cycle
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On March 21, 2022, Yang Weiwei, Zhao Yun and Yao Feng from Shanghai Jiaotong University published a joint communication titled "MAPK signalling-induced phosphorylation and subcellular translocation of PDHE1α promotes tumor immune evasion”, which found that PDH complex E1 subunit alpha (PDHE1α) is also located in the cytoplasm
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Intracellular PDHE1α interacts with IKKβ and protein phosphatase 1B, thereby promoting inhibition of the NF-κB pathway
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Intracellular PDHE1α can be phosphorylated at S327 by ERK2 and translocated into mitochondria
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Decreased cytoplasmic PDHE1α levels restored NF-κB signaling, while increased mitochondrial PDHE1α levels drove α-ketoglutarate production and facilitated detoxification of reactive oxygen species
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Synergistic activation of NF-κB and detoxification of reactive oxygen species promotes tumor cell survival and enhances drug resistance to cytotoxic lymphocytes
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Historically, low levels of PDHE1α phosphorylation have been associated with poor prognosis in lung cancer patients
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Taken together, our findings reveal a novel mechanism by which phosphorylation-dependent subcellular translocation of PDHE1α promotes tumor immune escape
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Tumor cells utilize multiple mechanisms to evade immune cell detection or suppress antitumor immune responses, such as downregulating MHC-I expression, preventing effector T cells from entering tumors, and altering the tumor microenvironment (TME) to suppress the activity of different types of immune cells
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Tumor antigen-specific cytotoxic T lymphocytes (CTLs), such as CD8+ T cells, are the main effectors of the antitumor cellular immune response
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CTLs enhance tumor immune sensitivity through direct perforin-dependent tumor cell killing and release of inflammatory cytokines, which play key roles in antitumor immunity, such as interferon gamma and tumor necrosis factor
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Interestingly, using a series of genome-wide-based functional screens, a recent study demonstrated that tumor necrosis factor-mediated bystander killing is a potent T-cell effector mechanism capable of killing antigen-negative tumor cells, emphasizing The importance of cytokine signaling in driving antitumor immunity
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Cancer cells utilize metabolic rearrangements to maintain their high proliferation rates and energy demands
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The most characteristic metabolic phenotype observed in tumor cells is the Warburg effect, also known as aerobic glycolysis
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High-throughput substrates through glycolysis allow efficient shunting of carbon to key accessory biosynthetic pathways
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The tricarboxylic acid (TCA) cycle is a metabolic center necessary for ATP production and required precursors in many biosynthetic pathways
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While earlier studies suggested that cancer cells bypass the TCA cycle and primarily utilize aerobic glycolysis, new evidence suggests that cancer cells, especially those with uncontrolled expression of oncogenes and tumor suppressor genes, are heavily dependent on the TCA cycle for metabolism to generate energy and synthesize macromolecules
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In contrast, how TCA cycle metabolism is reprogrammed to help tumor cells evade immune destruction is unclear
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Mechanism of PDHE1αPs327 to promote tumor immune escape linked to amino acid metabolism
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The PDH complex consists of PDH (E1), dihydrosulfamide transacetylase (E2) and dihydrosulfamide dehydrogenase (E3)
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PDH kinase (PDK1-4)-mediated phosphorylation of E1 subunit alpha (PDHE1α) at ​​serine (S) 232, 293 and 300 inhibits the activity of the PDH complex
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PDH phosphatases (PDP1 and PDP2) catalyze dephosphorylation to restore PDH activity
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Many transcription factors, including HIF, MYC, and estrogen-related receptors (ERRS), inhibit the activity of PDH by upregulating PDK expression, thereby promoting the Warburg effect and tumor growth
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The tumor suppressor gene P53 can inhibit the expression of PDK2 to activate PDH, thereby increasing the entry of pyruvate into mitochondria to accelerate oxidative respiration and inhibit tumorigenesis
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However, it has also been shown that phosphorylation of PDHA S295/314 by AMPK increases mitochondrial PDH activity, thereby driving the TCA cycle to promote tumor metastasis, suggesting a context-dependent role of PDH in cancer
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Furthermore, unlike its role in mitochondria, PDH is translocated into the nucleus under the action of serum and epidermal growth factor (EGF), where it regulates de novo synthesis of acetyl-CoA and maintains acetylation of core histones, to promote cell cycle progression and cell proliferation
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In conclusion, in this study, we explored the role of PDH in tumor immune evasion and demonstrated that activated oncogenic signaling induces subcellular translocation of PDHE1α, thereby enhancing tumor cell resistance to immunotherapy, thereby promoting Development of lung cancer
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