Upregulated expression of
immune checkpoint molecules correlates with exhausted phenotype and impaired function of cytotoxic T cells to evade host immunity. By disrupting the interaction of PD-L1 and PD1,
immune checkpoint inhibitors can restore immune system function against
cancer cells. Growing evidence have demonstrated
apigenin and
luteolin, which are
flavonoids abundant in common fruits and vegetables, can suppress growth and induce apoptosis of multiple types of
cancer cells with their potent anti-inflammatory,
antioxidant and anticancer properties. In this study, the effects and underlying mechanisms of
luteolin,
apigenin, and anti-PD-1 antibody combined with
luteolin or
apigenin on the PD-L1 expression and anti-
tumorigenesis in KRAS-mutant
lung cancer were investigated.
Luteolin and
apigenin significantly inhibited
lung cancer cell growth, induced cell apoptosis, and down-regulated the IFN-γ-induced PD-L1 expression by suppressing the phosphorylation of STAT3. Both
luteolin and
apigenin showed potent anti-
cancer activities in the H358 xenograft and
Lewis lung carcinoma model in vivo, and the treatment with monoclonal PD1 antibody enhanced the infiltration of T cells into
tumor tissues.
Apigenin exhibited anti-
tumor activity in Genetically engineered KRASLA2 mice. In conclusion, both
apigenin and
luteolin significantly suppressed
lung cancer with KRAS mutant proliferation, and down-regulated the IFN-γ induced PD-L1 expression. Treatment with the combination of PD-1 blockade and
apigenin/
luteolin has a synergistic effect and might be a prospective therapeutic strategy for NSCLC with KRAS-mutant.