Gastric cancer is the third leading cause of cancer-related mortality worldwide. Systemic chemotherapy is the main treatment option for advanced gastric cancer when the tumor is inoperable. Despite recent advances in chemotherapeutic agents, the prognosis of unresectable or recurrent gastric cancer remains extremely poor. In Japan, combination therapy including S-1 and cisplatin is the standard first-line treatment for advanced gastric cancer; however, the five-year survival rate remains very low. Lentinan, the backbone of beta-(1,3)-glucan with beta-(1,6) branches, an active ingredient purified from Shiitake mushrooms, has been approved as a biological response modifier for the treatment of gastric cancer. This agent has been used in combination with oral fluoropyrimidines to improve the overall survival of gastric cancer patients. A retrospective chart review on 138 metastatic gastric cancer patients receiving chemotherapy was performed in Nagoya Memorial Hospital from 1 September 2010 to 31 August 2015. 12 patients with liver metastases were treated by lentinan in combination with S-1-based chemotherapy. The rate of objective response was 42% (5/12) and the disease control rate was 83% (10/12) in response to chemo-immunotherapy using lentinan, with a median overall survival of 407 days (95% CI: 207–700 days).
Background: Despite recent therapeutic improvements, the prognosis of unresectable gastric cancer remains poor. Upregulation of programmed cell death ligand 1 (PD-L1) in tumor cells is believed to be an important mechanism to escape from the host's immune response. The expression of PD-L1 in tumors is regulated in a highly complex manner by various upstream signaling molecules, depending on the cell type. Given that the efficacy of chemotherapeutic agents for metastatic gastric cancer is limited due to immune escape caused by enhanced PD-L1 expression, PD-1/PD-L1 targeted immunotherapy may be a promising alterative for chemotherapy. However, immune checkpoint inhibitor monotherapy has shown clinical benefits in less than 20% of patients with gastric cancer and its underlying mechanism remains to be elucidated. On the other hand, lentinan, a β-glucan purified from Shiitake mushrooms, has significant immune-stimulating effects and has been reported to improve survival in patients with metastatic gastric cancer receiving chemotherapy. In the current study we investigated the mechanism by which lentinan increases the chemotherapeutic efficacy by focusing on the expression of PD-L1.Methods: To evaluate the effects of lentinan as well as antineoplastic agents, the expression of PD-L1 and associated molecules was analyzed by real-time polymerase chain reaction and western blotting using the human gastric cancer cell lines, NUGC3, MKN1, and MKN45.Results: Treatment with either cisplatin or oxaliplatin dose-dependently enhanced PD-L1 mRNA and protein expression through the mitogen-activated protein kinase (MAPK) pathway in gastric cancer cells. However, lentinan treatment inhibited the platinum drug-stimulated expression of PD-L1 in gastric cancer cells mainly by suppressing MAPK signaling without affecting the phosphatidylinositol-3 kinase/AKT pathway or transcription factors.Conclusions: Platinum-based drugs enhanced the expression of PD-L1 via the MAPK pathway in gastric cancer cells. Lentinan downregulated PD-L1 expression induced by either cisplatin or oxaliplatin, suggesting that a combination of this β-glucan and platinum-based chemotherapy could restore the chemosensitivity of cells.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.