Abstract
Background and AimsPyruvate kinase M2 (PKM2) is an essential regulator of the Warburg effect, but its biological function promoting immune escape of hepatocellular carcinoma (HCC) is unclear.MethodsGEPIA web tool and immunohistochemistry (IHC) analysis were employed to evaluate the clinical relevance of PKM2 in HCC patients. Both in vitro CCK-8, colony formation, and transwell assays, and in vivo xenografts were performed to evaluate the malignancy of HCC cells. PKM2 and PD-L1 levels were examined by Western blot, qRT-PCR, and IHC. The role of PKM2 on in vivo immune response was also investigated.ResultsPKM2 was significantly upregulated in HCC and associated with a poor prognosis of HCC patients. Knockdown of PKM2 inhibited in vitro proliferation, migration, and invasion of HCC cells, as well as in vivo tumor growth. Strikingly, PKM2 showed a strong correlation with the expression of immune inhibitory cytokines and lymphocyte infiltration in HCC. The overexpression of PKM2 sensitized HCC to immune checkpoint blockade, which enhanced IFN-γ positive CD8 T cells in HCC mice models.ConclusionPKM2 might be a predictor and a potential therapeutic target for immune checkpoint inhibitors in HCC.
Highlights
As one of the most common human malignancies, hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths worldwide [1]
The results showed that the mRNA levels of Pyruvate kinase M2 (PKM2) in HCC tissues were significantly higher than that in paraneoplastic tissues (Figure 1A)
The survival curves showed that a higher PKM2 level was significantly associated with poor prognosis of HCC patients (Figure 1C)
Summary
As one of the most common human malignancies, hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths worldwide [1]. In addition to some multikinase inhibitors such as Lenvatinib and Sorafenib have been proved to be standard treatment, recently, PD-1/PD-L1 blockade therapy have achieved remarkable success. Their efficacy is PKM2 Drives Hepatocellular Carcinoma Progression limited with less than 20% of patients who would benefit from them [2, 3]. Previous studies found that IL-22, produced by immune cells including T cells and NK cells, could promote oxidative phosphorylation and glycolysis and drive metabolic adaptive reprogramming [12]. Pyruvate kinase M2 (PKM2) is an essential regulator of the Warburg effect, but its biological function promoting immune escape of hepatocellular carcinoma (HCC) is unclear
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