Abstract
Natural polyphenolic compounds of grapes and their seeds are thought to be therapeutic adjuvants in a variety of diseases, including cancer prevention. This study was carried out to investigate the effect of grape phenolic compounds on the regulation of cancer-mediated immune suppression. Laricitrin exhibits the greatest potential to ameliorate the suppressive effects of lung cancer on dendritic cells’ (DCs’) differentiation, maturation and function. Human lung cancer A549 and CL1-5 cells change the phenotype of DCs that express to high levels of IL-10 and prime T cells towards an immune suppression type-2 response (Th2). Laricitrin treatment stimulated DC differentiation and maturation in the condition media of cancer cells, a finding supported by monocyte marker CD14's disappearance and DC marker CD1a's upregulation. Laricitrin decreases expression of IL-10 in cancer-conditioned DCs, and subsequently switches CD4+ T cell response from Th2 to Th1 in vitro and in vivo. Reversal of laricitrin on lung cancer-induced DCs’ paralysis was via inhibiting the phosphorylation of signal transducer and activator of transcription 3 (STAT3). Laricitrin also potentiated the anticancer activity of cisplatin in mouse models. Thus, laricitrin could be an efficacious immunoadjuvant and have a synergistic effect when combined with chemotherapy.
Highlights
Lung cancer is one of the leading causes of cancer mortality in the world [1]
This study demonstrates that laricitrin provides the highest level of efficacy to improve lung cancer-mediated dendritic cells’ (DCs) suppression through the down-regulation of the signal transducer and activator of transcription 3 (STAT3)/IL-10 signaling pathway
Since the combination of chemotherapy and immunotherapy is considered synergistic and enhances the clinical response, we evaluated whether laricitrin could synergize with cisplatin, a commonly used drug for treating lung cancer, to produce more powerful antitumor effects
Summary
In spite of aggressive treatment with surgery, radiation and chemotherapy, long-term survival rates remain low for lung cancer patients [2]. Cancer actively develops diverse mechanisms, such as producing immunosuppressive factor to attenuate antitumor immunity developed by the host, thereby limiting the success of immunotherapy [4]. Identification and overcoming of the multiple mechanisms of cancermediated immune suppression can provide a novel strategy for new lung cancer therapies. As a www.impactjournals.com/oncotarget result, DCs fail to activate cancer-reactive T cells and/ or skew cytokine production from type-1 response (Th1) towards a Th2 response [9, 10]. Dysfunctional DCs are found in patients with various cancers and in experimental mice with transplanted or spontaneous malignancies [11, 12]. Development of agents that improves cancermediated DCs dysfunction can provide new therapies for cancer treatment
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