Abstract
Pyruvate kinase M2 as a key rate-limiting enzyme in glycolysis, it plays a critical role in metabolic reprogramming and carcinogenesis. However, whether PKM2 can promote immunosuppressive microenvironment formation remains unknown in head and neck squamous cell carcinoma (HNSCC). PKM2 expression was detected using immunohistochemical staining. The biological functions of PKM2 were investigated in vitro and in vivo. Lactate production and the expression of Galectin-9, a critical immunosuppression molecule, were detected after PKM2 knockdown and overexpression in HNSCC cells. The mechanism of lactate regulating Galectin-9 expression through NF-κB signaling was explored in vitro. Overexpression of PKM2 correlates with poor prognosis in HNSCC patients. Silencing PKM2 markedly inhibits proliferation and metastasis capacity in vivo and in vitro, and vice versa. The glycolysis and glycolytic capacity are significantly decreased after PKM2 silencing. Lactate secretion induced by PKM2 significantly promotes migration and invasion capacity. Furthermore, a positive correlation between PKM2 and Galectin-9 expression is observed in HNSCC tissues. The induction of Galectin-9 expression by PKM2 can be affected by a lactate transporter inhibitor. Mechanically, lactate impeded the suppressive transcriptional complex formation of NF-κB and histone deacetylase 3 (HDAC3), which released the transcription of Galectin-9 mediated by NF-κB signaling. Our findings demonstrate that lactate produced by PKM2 upregulation promotes tumor progression and Galectin-9-mediated immunosuppression via NF-κB signaling inhibition in HNSCC, which bridges metabolism and immunosuppression. The novel PKM2-lactate-Galectin-9 axis might be a potential therapeutic target in HNSCC.
Highlights
Head and neck cancer is the eighth most common cause of cancer death worldwide [1] and head and neck squamous cell carcinoma (HNSCC) accounts for most of those [2]
Overexpression of PKM2 correlates with poor prognosis in HNSCC patients Firstly, we detected the PKM2 expression in HNSCC tissues and normal oral mucosa using immunohistochemical staining
We found that HNSCC patients with high PKM2 expression had worse outcomes in The Cancer Genome Atlas (TCGA) dataset (Fig. 1C, P = 0.022)
Summary
Head and neck cancer is the eighth most common cause of cancer death worldwide [1] and head and neck squamous cell carcinoma (HNSCC) accounts for most of those [2]. Galectin‐9, a member of the β‐galactoside lectin family, is involved many processes of T cell‐mediated diseases and immunomodulation of macrophages [6] It is a novel and critical checkpoint molecule on tumor surfaces that binds to T cell immunoglobulin and mucin domaincontaining protein 3 (TIM-3) on immune cells to inhibit the killing effect of immune cells [7]. Tumor microenvironment acidification drives immune escape by destroying the killing function of T and natural killer (NK) cells [8]. It means cancer cells could escape from immune surveillance by increasing lactate output [9].
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