Echinacoside inhibits tumor immune evasion by downregulating inducible PD-L1 and reshaping tumor immune landscape in breast and colorectal cancer.

BACKGROUND: Targeting PD-L1 has become a crucial approach in tumor immunotherapy. Echinacoside (ECH) is a natural compound known for its extensive biological activities, its impact on antitumor immunity remains uncertain.

PURPOSE: This work was designed to assess the effects of ECH on the PD-L1/PD-1-mediated tumor immune evasion and its underlying mechanisms.

METHODS: Flow cytometry and RT-qPCR were utilized to explore the influence of ECH on PD-L1 expression. Western blot was employed to examine the mechanism by which ECH might modulate PD-L1 expression. Flow cytometry was conducted to evaluate the influence of ECH therapy, or the synergistic effects of ECH combined with immune checkpoint blockade (ICB) on tumor immune microenvironment (TIME) in tumor-burden mice. Blood biochemistry tests were used to evaluate the safety of ECH treatment.

RESULTS: ECH downregulated both the protein and mRNA expression levels of IFN-γ-induced PD-L1 through JAK/STAT1/IRF1 signaling pathway. ECH treatment upregulated the infiltration of IFN-γ+CD8+ T cells and Ki-67+CD8+ T cells, lowered the frequency of TIM-3+PD-1+ T cells, promoted the infiltration of effector CD4+ T cells and total CD8+ T cells while suppressed the percentage of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSC). Moreover, the combination of ECH and anti-PD-1 or anti-CTLA-4 therapy exhibited synergistic anti-tumor effects, reshaping TIME. Blood biochemistry tests unveiled that ECH did not show additional toxicity.

CONCLUSION: ECH upregulates the expression of inducible PD-L1 through the JAK/STAT1/IRF1 signaling pathway, enhances T cell function, and reshapes the tumor immune landscape into an anti-tumor phenotype. Importantly, ECH markedly enhances the efficacy of ICB treatment, indicating its potential application in anti-tumor therapy.