Programmed death ligand 1 promotes lymph node metastasis and glucose metabolism in cervical cancer by activating integrin β4/SNAI1/SIRT3 signaling pathway

Although PD-L1 has been shown to play a well-characterized role in inhibiting antitumor immunity via engagement of its receptor PD-1 in T lymphocytes, little is known about the tumor cell-intrinsic function of PD-L1 and its association with prognosis. Here, we investigate this issue and dissect the molecular mechanisms underlying the role of PD-L1 in glucose metabolism, proliferation, migration, and invasion in human cervical cancer cells. As a result, we found that PD-L1 overexpression in cervical cancer cells increases glucose metabolism and metastasis-related behaviors. Mechanistically, PD-L1 bound directly to integrin β4 (ITGB4), activating the AKT/GSK3β signaling pathway and consequently inducing the expression of the transcriptional repressor SNAI1. SNAIL in turn influenced the expression of genes involved in the epithelial-to-mesenchymal transition and regulated glucose metabolism by inhibiting SIRT3 promoter activity. High expression of PD-L1 and ITGB4 in human cervical carcinomas was significantly associated with lymph node metastasis and poor prognosis. Finally, 18F-fluorodeoxyglucose microPET/CT and bioluminescence imaging analyses of cervical xenograft tumors in mice revealed that PD-L1 overexpression markedly increases tumor glucose uptake and promotes lymph node metastasis. Together, these results demonstrate that PD-L1 can promote the growth and metastasis of cervical cancer by activating the ITGB4/SNAI1/SIRT3 signaling pathway, and also suggest the possibility of targeting PD-L1 and its downstream effectors as a potential approach for interfering with cervical cancer growth and metastasis.