In a study published in Nature Metabolism, the groups of Drs. YANG Weiwei and ZHAO Yun from the Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology of the Chinese Academy of Sciences, reported the unique role and mechanism of PDHE1α, the key metabolic enzyme linking glycolysis and tricarboxylic acid cycle, in tumor immune evasion.
The treatment of lung cancer remains a great challenge. Although antibody-directed therapies against immune checkpoints targeting programmed death-1 (anti-PD-1) and targeting programmed death-ligand 1 (anti-PD-L1) therapies, for example, have shown remarkable success in many malignancies and already play a major role in the management of advanced lung cancer, not all PD-L1-positive patients benefit from anti-PD-1 therapy. Resolving the resistance of cancer cells to anti-PD-1 therapy will be of great significance for cancer treatment.
Pyruvate dehydrogenase (PDH) complex catalyzes the rate-limiting step during the pyruvate decarboxylation in mitochondria, converting pyruvate into acetyl-CoA in mitochondria, thereby linking the tricarboxylic acid (TCA) cycle with glycolysis, as well as with lipid and amino acid metabolism. The researchers in this study found that PDH complex E1 component subunit α (PDHE1α), normally localized in the mitochondria matrix, is also abundantly localized in cytosol. Cytosolic PDHE1α interacts with IKKβ and inhibits its activation and subsequent NF-κB signaling through PPM1B-mediated IKKβ serine (S) 177/181 dephosphorylation, thereby promoting inflammatory cytokines or cytotoxic T lymphocytes (CTLs)-induced tumor cell death.
However, upon the activation of oncogenic signaling, such as mitogen-activated protein kinase (MAPK), in lung cancer cells, cytosolic PDHE1α is phosphorylated at S327 by ERK2 and translocated into mitochondria, which leads to the reactivation of NF-κB signaling as well as reactive oxygen species (ROS) detoxification mediated by mitochondria-translocated PDHE1α-produced α-ketoglutarate (α-KG), thereby promoting tumor cell survival after CTLs killing, tumor immune evasion and anti-PD-1 therapy resistance.
Additionally, immunohistochemistry analysis of human lung cancer patient samples indicated that the levels of PDHE1α S327 phosphorylation or cytosolic PDHE1α protein are strongly associated with the malignancy and prognosis of lung cancer.
This study reveals the unique role of PDHE1α in tumor immune evasion and demonstrates the mechanism underlying phosphorylation-dependent subcellular translocation of PDHE1α and the dual functions of such translocation, suggesting that abrogating its phosphorylation can improve the efficacy of immunotherapy for lung cancer as well as the prognostic potential of its phosphorylation level to predict the response of anti-PD-1 therapies.
YAO Feng’s group from Shanghai Chest Hospital, Shanghai Jiao Tong University also participated in the study.