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

Abstract

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, F-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.

ARID1A knockdown triggers epithelial‐mesenchymal transition and carcinogenesis features of renal cells: role in renal cell carcinoma

“…6A-F). This data was consistent with several lines of evidence, highlighting the roles of SNAI1 in EMT phenotypes, invasion, metastasis, and therapeutic resistance of several cancers (52)(53)(54)(55). SNAI1 can be triggered by TGF-b1, a known inducer of EMT.…”

Integrin β4–Targeted Cancer Immunotherapies Inhibit Tumor Growth and Decrease Metastasis

“…We also examined the ability of ITGB4 immunotherapy to augment the efficacy of anti-PD-L1 immune checkpoint blockade because PD-L1 was expressed in our tumor cell models. Furthermore, Wang and colleagues reported that PD-L1 can promote the growth and metastasis of tumor by activating the ITGB4/SNAI1/SIRT3 signaling pathway, suggesting another potential mechanism of synergy between these pathways (45). Our data indicate that anti-PD-L1 antibody significantly augmented the therapeutic efficacy of ITGB4-DC vaccine and ITGB4 BiAb-armed T-cell adoptive transfer in both 4T1 and SCC7 models.…”

Clinical Significance of Circulating Exosomal PD-L1 and Soluble PD-L1 in Nasal-type NK/T-cell Lymphoma Patients Receiving VIPD Containing Chemotherapy

“…Our data demonstrated that a high level of plasma exoPD-L1 was associated with an elevated baseline SUVmax. PD-L1 expression is associated with glucose metabolism in various cancers, such as lung cancer and cervical cancer [29,30]. The SUVmax in PET/CT was signi cantly higher in the high exoPD-L1 group and high sPD-L1 group, possibly because lymphoma cells may release PD-L1 to promote glycometabolism.…”