Elevation of spermine remodels immunosuppressive microenvironment through driving the modification of PD-L1 in hepatocellular carcinoma

Abstract

Background Spermine is frequently elevated in tumor tissues and body fluids of cancer patients and is critical for cancer cell proliferation, migration and invasion. However, the immune functions of spermine in hepatocellular carcinoma progression remains unknown. In the present study, we aimed to elucidate immunosuppressive role of spermine in hepatocellular carcinoma and to explore the underlying mechanism. Methods Whole-blood spermine concentration was measured using HPLC. Human primary HCC tissues were collected to examine the expression of CaSR, p-Akt, β-catenin, STT3A, PD-L1, and CD8. Mouse model of tumorigenesis and lung metastasis were established to evaluate the effects of spermine on hepatocellular carcinoma. Western blotting, immunofluorescence, real time PCR, digital Ca2+ imaging, and chromatin immunoprecipitation assay were used to investigate the underlying mechanisms by which spermine regulates PD-L1 expression and glycosylation in hepatocellular carcinoma cells. Results Blood spermine concentration in the HCC patient group was significantly higher than that in the normal population group. Spermine could facilitate tumor progression through inducing PD-L1 expression and decreasing the CD8+ T cell infiltration in HCC. Mechanistically, spermine activates calcium-sensing receptor (CaSR) to trigger Ca2+ entry and thereby promote Akt-dependent β-catenin stabilization and nuclear translocation. Nuclear β-catenin induced by spermine then activates transcriptional expression of PD-L1 and N-glycosyltransferase STT3A, while STT3A in turn increases the stability of PD-L1 through inducing PD-L1 protein N-glycosylation in HCC cells. Conclusions This study reveals the crucial function of spermine in establishing immune privilege by increasing the expression and N-glycosylation of PD-L1, providing a potential strategy for the treatment of hepatocellular carcinoma.

Spermine Synthase Engages in Macrophages M2 polarization to Sabotage Antitumor Immunity in Hepatocellular Carcinoma

“…Generally speaking, spermidine is reckoned to be a protective factor for antitumor immunity, while putrescine and spermine are inclined to aggravate immune escape (40,41). To be speci c, as the metabolic hub, liver holds an elevated SMS expression, and the concentration of spermine in blood is higher under the circumstances of HCC (42,43). Here, by ultra ltrating the TSN, we determined that spermine functions as the exact regulator in response to upregulated SMS.…”

Post-translational modifications and immune responses in liver cancer

“…One notable finding is that spermine, a natural polyamine compound, can activate β-catenin, a protein involved in cell adhesion and signaling pathways. Activation of β-catenin leads to the transcriptional expression of PD-L1 and N-glycosyltransferase STT3A ( 68 ). Targeting STT3A might be a potential strategy for improving the response to checkpoint inhibitors in HCC patients.…”

Polyamines: the pivotal amines in influencing the tumor microenvironment

“…These results support the hypothesis that increased polyamine synthesis or uptake expressly in T-cells can help support T-cell function and decrease immunosuppression and tumor cell immune evasion. In the context of hepatocellular carcinoma, spermine exerts an immunosuppressive role by elevating N -glycosylation and expression of PD-L1 through Akt-dependent β-catenin stabilization [ 20 ]. This upregulation of PD-L1 encourages immune evasion by the cancer cells and decreases efficacy of immunotherapies.…”