Nat Metab: Yang Weiwei and Yao Feng's team collaborated to discover a new metabolic mechanism of immune escape from lung cancer

The research team of Yang Weiwei from the Center for Excellence in Molecular and Cell Science of the Chinese Academy of Sciences found that oncogenic signals such as MAPK promote tumor immune escape by regulating the subcellular translocation of pyruvate dehydrogenase PDHE1α
.

On March 22, 2022, Beijing time, the international academic journal "Nature-Metabolism" published the research results online
.

Researcher Yang Weiwei and Zhao Yun from the Center of Excellence for Molecular Cells and Yao Feng, Deputy Chief Physician of the Chest Hospital Affiliated to Shanghai Jiaotong University, are the co-corresponding authors of the paper

The research team of Yang Weiwei from the Center for Excellence in Molecular and Cell Science of the Chinese Academy of Sciences found that oncogenic signals such as MAPK promote tumor immune escape by regulating the subcellular translocation of pyruvate dehydrogenase PDHE1α
.

immunity

On March 22, 2022, Beijing time, the international academic journal "Nature-Metabolism" published the research results online
.

Researcher Yang Weiwei and Zhao Yun from the Center of Excellence for Molecular Cells and Yao Feng, Deputy Chief Physician of the Chest Hospital Affiliated to Shanghai Jiaotong University, are the co-corresponding authors of the paper

Lung cancer is the most common cause of cancer-related death worldwide, and its treatment remains a formidable challenge
.

Although targeted therapy against immune checkpoints (anti-PD-1 therapy, anti-PD-L1 therapy, etc.

lung cancer

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

tumor immunity

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

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 a new mechanism for phosphorylation to regulate PDHE1α subcellular translocation and PDHE1α subcellular translocation to regulate tumor immune escape; suggesting that inhibition of PDHE1α phosphorylation can Block tumor immune escape and improve the efficacy of tumor immunotherapy

This research work has been funded by the National Key R&D Program, the National Natural Science Foundation of China, and the Youth Basic Research Project of the Chinese Academy of Sciences

Natural Science Foundation

Original source:

Zhang, Y.