Rationale: Abnormal expression of programmed death-1 (PD-1) ligand-1(PD-L1) in
cancer cells plays a crucial role in
cancer immune evasion and progression. The
immune checkpoint molecules PD-1 and PD-L1 have been targeted for
cancer treatment with significant benefits for
cancer patients. However, the response rate is relatively low in certain types of
cancer and the underlying mechanism remains poorly understood. Better understanding of the molecular mechanism of PD-L1 expression regulation in
cancer cells is urgently needed to improve the treatment response rate and overall survival of patients. Fructose-1, 6-biphosphatase (FBP1) is a key
enzyme in gluconeogenesis and is implicated in human
cancer due to its frequent loss in various
cancer types. Methods: Expression of FBP1 and PD-L1 was analyzed in various
cancer cell lines. Western blot and RT-qPCR were performed to determine whether FBP1 regulates PD-L1 expression. Co-immunoprecipitation and
glutathione S-transferase (GST) pulldown assay were employed to define the underlying regulatory mechanisms. Immunohistochemistry was conducted to determine the correlation between FBP1 and PD-L1 expression in a cohort of patients. A
cancer syngeneic mouse model was utilized to examine how FBP1 affects
tumor immunity. Results: We demonstrated that in a manner independent of its enzymatic activity FBP1 downregulates the expression of PD-L1 in various cell lines of different
cancer types including pancreatic and
prostate cancer. We further showed that this regulation occurs at the transcriptional level and is mediated by FBP1 inhibition of signal transducer and activator of transcription-3 (STAT3)-dependent PD-L1 transcription. Moreover, FBP1 and
PD-L1 protein expression were negatively correlated in pancreatic ductal
adenocarcinoma (PDAC) specimens from a cohort of patients. Most importantly, we demonstrated that decreased FBP1 expression promotes
tumor growth and resistance to
immune checkpoint blockade therapy in mice. Conclusions: Our findings reveal a new
tumor suppressor function of FBP1 in inhibiting PD-L1 expression and enhancing
cancer immunity. They also suggest that FBP1-deficient human
cancers could be therapeutically targeted by PD-1/PD-L1-based
immune checkpoint blockade therapy.