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Editor | Wang Duoyu Typography | Shui Chengwen Lung cancer is the most common cause of cancer-related death worldwide, and the treatment of lung cancer remains a huge challenge
.
Although targeted therapy against immune checkpoints (anti-PD-1 therapy, anti-PD-L1 therapy, etc.
) has shown remarkable results in the treatment of many malignant tumors, and has played an important role in the treatment of advanced lung cancer, Not all patients with PD-1-positive lung cancer benefit from anti-PD-1 therapy
.
Addressing the resistance of tumor cells to anti-PD-1 therapy will have important clinical implications
.
The tricarboxylic acid cycle (TCA cycle) is an important metabolic hub in cells and is essential for the production of ATP and the supply of precursors in many biosynthetic pathways
.
Although earlier studies suggested that cancer cells bypass the TCA cycle and primarily utilize aerobic glycolysis; emerging evidence suggests that certain cancer cells, especially those with uncontrolled expression of proto-oncogenes and tumor suppressor genes, are severely Rely on the TCA cycle for energy production and synthesis of biological macromolecules
.
However, whether and how the TCA cycle is involved in tumor immune escape and resistance to anti-PD-1 therapy remains unclear
.
On March 21, 2022, Yang Weiwei's research group from the Center for Excellence in Molecular and Cellular Science, Chinese Academy of Sciences, together with Researcher Zhao Yun and Yao Feng, Deputy Chief Physician of the Chest Hospital Affiliated to Shanghai Jiaotong University, published a paper in the journal Nature Metabolism entitled: MAPK signalling-induced phosphorylation and Research paper on subcellular translocation of PDHE1α promotes tumor immune evasion
.
This study found that oncogenic signals such as MAPK promote tumor immune escape by regulating the subcellular translocation of pyruvate dehydrogenase PDHE1α
.
In this study, the researchers performed immunofluorescence staining experiments on tumor tissue from lung cancer patients
.
Unexpectedly, they found that a metabolic enzyme originally localized to the mitochondrial matrix, linking glycolysis and the TCA cycle, the alpha subunit of the E1 component of the pyruvate dehydrogenase complex (PDHE1α), has an abundant cytoplasmic localization; cytoplasmic PDHE1α The level is positively correlated with the patient's prognosis
.
Further studies found that cytoplasmic PDHE1α attenuated the activation of NF-κB signaling pathway by promoting the dephosphorylation of IKKβ S177/181 (a key phosphorylation site for IKKβ activation) by phospholipase PPM1B, and enhanced inflammatory factors and cytotoxic T.
Tumour cell death induced by lymphocytes (CTLs)
.
However, activation of oncogenic signaling such as MAPK resulted in phosphorylation of cytoplasmic PDHE1α S327 by ERK2 and translocation to mitochondria; decreased levels of cytoplasmic PDHE1α restored the activation of NF-κB signaling; meanwhile, mitochondrial PDHE1α The increase of α-ketoglutarate increased the content of α-ketoglutarate and promoted the detoxification of ROS in tumor cells stimulated by inflammatory factors
.
Activation of NF-κB and scavenging of ROS together promote the survival of tumor cells under the stimulation of inflammatory factors, enhance the tolerance of tumor cells to CTLs, and ultimately promote tumor immune escape and resistance to anti-PD-1 therapy.
.
In addition, the phosphorylation level of PDHE1α S327 in tumor tissues of lung cancer patients was correlated with cytoplasmic PDHE1α level, ERK2 activity and NF-κB activation; the cytoplasmic PDHE1α level or PDHE1α S327 phosphorylation level was correlated with the malignancy and prognosis of lung cancer patients
.
Figure: MAPK signaling-induced phosphorylation and translocation of PDHE1α promotes tumor immune escape.
This work discovered a new function of PDHE1α subcellular translocation in tumor immune escape; revealed that phosphorylation regulates PDHE1α subcellular translocation and PDHE1α subcellular translocation A new mechanism for the regulation of tumor immune escape; suggesting that inhibiting the phosphorylation of PDHE1α can block tumor immune escape and improve the efficacy of tumor immunotherapy
.
Researcher Yang Weiwei and Zhao Yun from the Center of Excellence for Molecular Cells of the Chinese Academy of Sciences and Yao Feng, deputy chief physician of the Chest Hospital Affiliated to Shanghai Jiaotong University, are the co-corresponding authors of the paper
.
Associate researcher Zhang Yajuan and Ph.
D.
student Zhao Ming of Yang Weiwei's group are the co-first authors
.
Paper link: https:// Open for reprinting, welcome to forward to Moments and WeChat groups
.
Although targeted therapy against immune checkpoints (anti-PD-1 therapy, anti-PD-L1 therapy, etc.
) has shown remarkable results in the treatment of many malignant tumors, and has played an important role in the treatment of advanced lung cancer, Not all patients with PD-1-positive lung cancer benefit from anti-PD-1 therapy
.
Addressing the resistance of tumor cells to anti-PD-1 therapy will have important clinical implications
.
The tricarboxylic acid cycle (TCA cycle) is an important metabolic hub in cells and is essential for the production of ATP and the supply of precursors in many biosynthetic pathways
.
Although earlier studies suggested that cancer cells bypass the TCA cycle and primarily utilize aerobic glycolysis; emerging evidence suggests that certain cancer cells, especially those with uncontrolled expression of proto-oncogenes and tumor suppressor genes, are severely Rely on the TCA cycle for energy production and synthesis of biological macromolecules
.
However, whether and how the TCA cycle is involved in tumor immune escape and resistance to anti-PD-1 therapy remains unclear
.
On March 21, 2022, Yang Weiwei's research group from the Center for Excellence in Molecular and Cellular Science, Chinese Academy of Sciences, together with Researcher Zhao Yun and Yao Feng, Deputy Chief Physician of the Chest Hospital Affiliated to Shanghai Jiaotong University, published a paper in the journal Nature Metabolism entitled: MAPK signalling-induced phosphorylation and Research paper on subcellular translocation of PDHE1α promotes tumor immune evasion
.
This study found that oncogenic signals such as MAPK promote tumor immune escape by regulating the subcellular translocation of pyruvate dehydrogenase PDHE1α
.
In this study, the researchers performed immunofluorescence staining experiments on tumor tissue from lung cancer patients
.
Unexpectedly, they found that a metabolic enzyme originally localized to the mitochondrial matrix, linking glycolysis and the TCA cycle, the alpha subunit of the E1 component of the pyruvate dehydrogenase complex (PDHE1α), has an abundant cytoplasmic localization; cytoplasmic PDHE1α The level is positively correlated with the patient's prognosis
.
Further studies found that cytoplasmic PDHE1α attenuated the activation of NF-κB signaling pathway by promoting the dephosphorylation of IKKβ S177/181 (a key phosphorylation site for IKKβ activation) by phospholipase PPM1B, and enhanced inflammatory factors and cytotoxic T.
Tumour cell death induced by lymphocytes (CTLs)
.
However, activation of oncogenic signaling such as MAPK resulted in phosphorylation of cytoplasmic PDHE1α S327 by ERK2 and translocation to mitochondria; decreased levels of cytoplasmic PDHE1α restored the activation of NF-κB signaling; meanwhile, mitochondrial PDHE1α The increase of α-ketoglutarate increased the content of α-ketoglutarate and promoted the detoxification of ROS in tumor cells stimulated by inflammatory factors
.
Activation of NF-κB and scavenging of ROS together promote the survival of tumor cells under the stimulation of inflammatory factors, enhance the tolerance of tumor cells to CTLs, and ultimately promote tumor immune escape and resistance to anti-PD-1 therapy.
.
In addition, the phosphorylation level of PDHE1α S327 in tumor tissues of lung cancer patients was correlated with cytoplasmic PDHE1α level, ERK2 activity and NF-κB activation; the cytoplasmic PDHE1α level or PDHE1α S327 phosphorylation level was correlated with the malignancy and prognosis of lung cancer patients
.
Figure: MAPK signaling-induced phosphorylation and translocation of PDHE1α promotes tumor immune escape.
This work discovered a new function of PDHE1α subcellular translocation in tumor immune escape; revealed that phosphorylation regulates PDHE1α subcellular translocation and PDHE1α subcellular translocation A new mechanism for the regulation of tumor immune escape; suggesting that inhibiting the phosphorylation of PDHE1α can block tumor immune escape and improve the efficacy of tumor immunotherapy
.
Researcher Yang Weiwei and Zhao Yun from the Center of Excellence for Molecular Cells of the Chinese Academy of Sciences and Yao Feng, deputy chief physician of the Chest Hospital Affiliated to Shanghai Jiaotong University, are the co-corresponding authors of the paper
.
Associate researcher Zhang Yajuan and Ph.
D.
student Zhao Ming of Yang Weiwei's group are the co-first authors
.
Paper link: https:// Open for reprinting, welcome to forward to Moments and WeChat groups
