Lycopene improves the efficiency of anti-PD-1 therapy via activating IFN signaling of lung cancer cells

Abstract

BackgroundMonoclonal antibodies targeting programmed death-1 receptor (PD-1) and its ligand (PD-L1) have been developed to treat cancers including lung cancer. In this study, we aimed to investigate whether lycopene could promote the effect of anti-PD-1 treatment on lung cancer.MethodsTumor formation assay was conducted. Immune reactions were assessed by detecting several cytokine levels using enzyme-like immunosorbent assay. T cell activity was analyzed using cytometry. The mechanism of lycopene action was investigated using Western blot, quantitative real-time polymerase chain reaction and bisulfite sequencing analysis.ResultsAfter the mice injected with Lewis lung carcinoma (LLC) cells were sacrificed, we found that combined lycopene and anti-PD-1 reduced the tumor volume and weight compared to control treatment. Cell apoptosis in the tumor tissues was significantly enhanced in mice with combined lycopene and anti-PD-1 treatment in comparison with those of either lycopene or anti-PD-1 alone. Furthermore, lycopene could assist anti-PD-1 to elevate the levels of interleukin (IL)-1 and interferon (IFN) γ while reduce the levels of IL-4 and IL-10 in the spleen of mice injected with LLC cells. Lycopene treatment increased the CD4+/CD8+ ratio in the spleen and promoted IFNγ-expressing CD8+ T cells in tumor tissues. Upon IFNγ stimulation, lycopene diminished PD-L1 expression via activating JAK and repressing phosphorylation of AKT.ConclusionOur results have demonstrated that lycopene could be used as a potential adjuvant drug to synergistically improve the efficiency of anti-PD-1 therapy.Electronic supplementary materialThe online version of this article (10.1186/s12935-019-0789-y) contains supplementary material, which is available to authorized users.

New Insights into Molecular Mechanism behind Anti-Cancer Activities of Lycopene

“…There was a significant increment observed in IL-2, IFNγ, CD4 + :CD8 + T cells ratio, percentage of IFNγ + /CD8 + T cells, percentage of perforin + /CD8 + T cell, percentage of granzyme B + /CD8 + T cell, gene expression of IFNβ, IFNγ, IRF1, IRF7, CXCL9 and CXCL10. Similar to the in vitro study, no change was observed in gene expression of DNMT1, DNMT3b, IRF3 and IRF8 [69].…”

“…In this experiment, lycopene managed to enhance IFNβ, IFNγ, IRF1, IRF7, CXCL9, CXCL10 while suppressing IL-4, IL-10, DMNT3a, methylation of IRF1, IRF7 promoters and most importantly, the tumor volume. Increment of CD4 + /CD8 + T cells ratio, percentage of IFNγ + /CD8 + T cell, percentage of perforin + /CD8 + T cell and percentage of granzyme B + /CD8 + T cell were reported, accompanied by no significant change in DNMT1 and DNMT3b [69]. Compiling these evidences depicted that lycopene could enhance activation and differentiation of T cells and T helper cells Th1/Th2 drift via suppression of IL-4 and upregulation of IFNγ, most probably by its ability to modulate cytokines, chemokines and interferons.…”

Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy

“…IFN-γ is indispensable for anti-PD-1 treatment due to its role in the fragility of Tregs [49,50]. Increased IFN can improve the efficacy of anti-pd-1 therapy [51].…”

Measurement of Lycopene Effectiveness on Lung and Kidney Cancer Cells by Quantitative 1h Magnetic Resonance Imaging in Vitro

“…In 1997, Talwar et al presented the effect of inflammation on the content of antioxidants, among others, lycopene in patients with nonsmall cell lung cancer (NSCLC) (21). In in vivo studies on mice, Jiang et al tested the effect of lycopene on improving the effect of monoclonal antibody therapy (22). Sheriff et al performed studies in rats that examined the effect of lycopene in preventing mitochondrial dysfunction during d-GalN / LPS-induced FHF (23).…”