Recently, Professor Lu Zhimin, a foreign academician of Academia Europaea, , Institute of Translational Medicine, Zhejiang University, /First Affiliated Hospital, and his team studied the expression level of PD-L1 in tumor cells under the conditions of high-level glycolysis . It was found that high sugar could promote PD-L1 expression.
Figure | Lu Zhimin (Source: Lu Zhimin)
Further, it found that this is related to the key enzyme in glycolysis - hexokinase 2. Hexokinase 2 (Hexokinase 2, HK2) is a key metabolic enzyme that catalyzes the first step reaction in the glycolytic pathway, phosphorylates glucose into glucose 6-phosphate and is mainly located on the outer membrane of the mitochondria.
Recently, a related paper was published on Cell Metabolism6Cell Metabolism. Lu Zhimin serves as the corresponding author of , and Guo Dong serves as the joint work [1].
Figure | Related papers (Source: Cell Metabolism)
Reviewer believes that this work discovered a new mechanism by which glycolysis promotes the immune escape of tumors and also discovered that the nutrient in the tumor microenvironment, namely glucose , can promote the expression of PD-L1, and the research results are exciting.
It is reported that a large number of gene mutations in the tumor and the unique microenvironment often lead to changes in the original function of metabolic enzymes and confer new non-metabolic enzyme functions.
This study is the sixth metabolic enzyme with protein kinase activity discovered by the laboratory after discovering the sugar metabolic enzymes PKM2 [2], PGK1 [3], KHK-A [4], PCK1 [5] and CHKα [6]. Protein kinase activity plays an important role in tumorigenesis and development. This series of research combined has changed the industry's traditional understanding of tumor metabolism.
In this work, the team first observed a significant increase in PD-L1 expression in many tumor cells, which aroused their interest, as it suggests that high levels of glycolysis may promote immune escape.
Immediately, the research team began to conduct in-depth research on this phenomenon. Then, they found that hexokinase 2 (HK2) played a key role in it, so it focused on the HK2 protein.
was detected by mass spectrometry, and the team found that IκBα is an interacting protein of HK2. More importantly, they found that HK2, as a protein kinase, phosphorylation of IκBα, leads to degradation of IκBα, activation of of NF-κB signaling pathway, and increased PD-L1 expression levels.
After studying the specific molecular mechanism, the researchers then verified it on the animal model. It was found that tumors grew more slowly after knockdown of HK2 and infiltrated more CD8+ T cells, the same phenotype was also seen on tumors expressing IκBα T291A.
In addition, they used Lonidamine, an inhibitor of hexokinase , combined with PD-1 monoclonal antibody to treat glioma in mice. They found that compared with PD-1 antibody alone, using Lonidamine and PD-1 antibody combined treatment can significantly improve the therapeutic effect of PD-1 antibody.
This research results also show that glycolysis plays a key role in promoting tumor immune escape. Related experiments have also confirmed that the use of hexokinase inhibitors combined with PD-1 monoclonal antibody can significantly improve the therapeutic effect of PD-1 antibodies.
This provides a new strategy for the use of PD-1 monoclonal antibody drugs in clinical practice, that is, the combination of drugs may have better effects on some tumors that are not significantly associated with PD-1 antibodies.
(Source: Cell Metabolism)
In the study, in order to verify the phosphorylation of IκBα by HK2 and find the specific site for HK2 to phosphorylate IκBα, the research team used protein spectrometry to identify it.
However, it was not found that the peptide was phosphorylated by HK2 at the beginning. After repeated analysis, it was found that the previous mass spectrometry was digested using trypsin , and there was no cleavage site for the trypsin in a long sequence in the IκBα protein.
So, they chose another protease -AspN- to digest the protein substrate, and finally successfully identified the phosphorylation site.
In addition, the research team also found that the binding of HK2 to IκBα and the function of protein kinase plays an important role in tumor immunization of . Therefore, finding some means to destroy the interaction between the two and thus inhibit the suppression of HK2 on tumor immunity will be the main content of their subsequent research.
Reference:
1.Guo, D., Tong, Y., Jiang, X., Meng, Y., Jiang, H., Du, L., ... & Lu, Z. (2022). Aerobic glycycolysis promotes tumor immunoe evaluation by hexokinase2-mediated phosphorylation of IκBα. Cell metabolism.
2.Nature, 2011, PMID: 22056988; Cell, 2012, PMID: 22901803; Molecular Cell, 2014, PMID: 24316223
3.Molecular Cell, 2016, 2017, 2019, PMID: 26942675, 28238651, 31492635
4.Nature Cell Biology, 2016, PMID:2708854; Science Advanceds, 2019, PMID:31032410
5.Nature, 2020, PMID:32322062
6.Molecular Cell, 2021, PMID: 34077757
