The effect of methylglyoxal and glyoxalase-1 metabolism on immune-mediated signaling and overall survival in biliary tract cancer

Introduction Methylglyoxal (MGO) is a cytotoxic metabolite that accumulates in chronic inflammation and cancer, leading to a pro-tumorigenic microenvironment with suppressive effects on immune therapy. Glyoxalase-1 (GLO1) is the rate-limiting enzyme to detoxify MGO and to prevent its accumulation. However, the metabolism of MGO and GLO1 and its effect on overall survival (OS) and immune-mediated signaling in biliary tract cancer (BTC) remains unknown.

Methods Immunohistochemical staining (semiquantitative evaluation) of GLO1 in resected BTCs from 245 patients, and its association with OS was performed. Investigation of MGO and GLO1 was conducted in BTC cell lines (EGI-1, TFK-1, and SNU-1079) using RNA techniques (qPCR) under treatment conditions (GLO1 inhibitor and chemotherapy with gemcitabine/cisplatin). In addition, knockdown of GLO1 (siRNA) and simultaneous treatment with MGO were conducted to analyze the effect on immune-mediated signaling pathways (STAT3, STAT6, and IL-6) and PD-L1 expression.

Results Nuclear staining of GLO1 was associated with better OS in intrahepatic BTC compared to no staining (p=0.018). Inhibition of GLO1 in BTC cell lines resulted in upregulation of IL-6. Treatment with gemcitabine and cisplatin resulted in upregulation of IL-6 and PD-L1. Knockdown of GLO1 led to the upregulation of immune-mediated signaling pathways (STAT3, STAT6 and IL-6). Simultaneous GLO1 knockdown with MGO treatment was associated with a concentration-dependent reduction in PD-L1 (35% less compared to no treatment).

Conclusions Nuclear GLO1 staining is associated with better survival in intrahepatic BTC. Impaired MGO-GLO1 metabolism may maintain a pro-tumorigenic immune-mediated microenvironment. Understanding these mechanisms may serve to improve immune therapy in BTC.

Publication History

Article published online:
23 January 2024