Abstract 2527: PD-L1 regulation by Dual Oxygenase 2 (DUOX2), a reactive oxygen species (ROS) producing enzyme in gastric cancers

Abstract Immune checkpoint inhibitors have shown outstanding activities in some cancers, but their efficacy is rather variable with limited long-term response in most patients while others do not respond well or even develop resistances. The oxidative state of the tumor and its microenvironment plays a critical role in this response and highlights the importance of better understanding the role of redox enzymes in response to immunotherapy. In fact, Reactive Oxygen Species (ROS) effectors can either up or down regulate PD-L1 expression depending on their targets and mechanisms of action. Our data indicate that DUOX2, an NADPH enzyme involved in the production of H2O2, is expressed in about forty percent of human gastric cancers and is significantly increased in esophageal cancers. Moreover, DUOX2 expression in human gastric and esophageal cancer cells corresponds to down regulation of the immune checkpoint PD-L1. Conversely, down regulation of DUOX2 increases PD-L1, HIF-1α and c-Myc expression in these cells. To better understand the role of DUOX2 in the production of ROS and how it interferes with the expressions of HIF-1α and PD-L1, we also evaluated its effects on the ROS scavenger glutathione (GSH) and the ROS generating Ceramide in cells expressing or not DUOX2. The down regulation of DUOX2 reduced by more than half Ceramide levels and significantly increased GSH levels. This is consistent with the known effect of H2O2 on Ceramide generation through sphingomyelin hydrolysis and H2O2 inhibitory effect on HIF-1α binding and accumulation of HIF-1α protein. Because HIF-1α is a known regulator of PD-L1, DUOX2 expression on some tumors could thus interfere with PD-L1 expression through generation of H2O2. Moreover, because HIF-1α and PD-L1 expression contribute to radio-resistance, DUOX2 expression could sensitize cancer cells to radiation therapy. On the other hand, tumors lacking DUOX2 expression would be expected to be more sensitive to immunotherapy targeting PD-1 and/or PD-L1. DUOX2 expression thus appears to hold significant potential as a valuable biomarker to guide therapeutic decisions regarding radiation or immuno-therapy. Citation Format: France Carrier, Mariana B. Martins. PD-L1 regulation by Dual Oxygenase 2 (DUOX2), a reactive oxygen species (ROS) producing enzyme in gastric cancers abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 2527.