Neutralization of NET-associated human ARG1 enhances cancer immunotherapy

by Selleckchem | Apr 09 2023

Myeloid cells can restrain antitumor immunity by metabolic pathways, such as the degradation of l-arginine, whose concentrations are regulated by the arginase 1 (ARG1) enzyme. Results from preclinical studies indicate the important role of arginine metabolism in pancreatic ductal adenocarcinoma (PDAC) progression, suggesting a potential for clinical application; however, divergent evolution in ARG1 expression and function in rodents and humans has restricted clinical translation. To overcome this dichotomy, here, we show that neutrophil extracellular traps (NETs), released by spontaneously activated neutrophils isolated from patients with PDAC, create a microdomain where cathepsin S (CTSS) cleaves human (h)ARG1 into different molecular forms endowed with enhanced enzymatic activity at physiological pH. NET-associated hARG1 suppresses T lymphocytes whose proliferation is restored by either adding a hARG1-specific monoclonal antibody (mAb) or preventing CTSS-mediated cleavage, whereas small-molecule inhibitors are not effective. We show that ARG1 blockade, combined with immune checkpoint inhibitors, can restore CD8+ T cell function in ex vivo PDAC tumors. Furthermore, anti-hARG1 mAbs increase the frequency of adoptively transferred tumor-specific CD8+ T cells in tumor and enhance the effectiveness of immune checkpoint therapy in humanized mice. Thus, this study shows that extracellular ARG1, released by activated myeloid cells, localizes in NETs, where it interacts with CTSS that in turn cleaves ARG1, producing major molecular forms endowed with different enzymatic activity at physiological pH. Once exocytosed, ARG1 activity can be targeted by mAbs, which bear potential for clinical application for the treatment of PDAC and require further exploration.

Comments：

The passage describes a study that investigates the role of neutrophil extracellular traps (NETs) and cathepsin S (CTSS) in regulating the activity of arginase 1 (ARG1) in pancreatic ductal adenocarcinoma (PDAC). Myeloid cells, such as neutrophils, can limit the immune response against tumors by metabolizing l-arginine through ARG1. However, the expression and function of ARG1 differ between rodents and humans, which complicates the translation of preclinical studies to the clinic.

The study shows that NETs released by spontaneously activated neutrophils from PDAC patients create a microdomain where CTSS cleaves human (h)ARG1 into different molecular forms with enhanced enzymatic activity at physiological pH. The resulting NET-associated hARG1 suppresses T lymphocytes, which can be restored by either adding a hARG1-specific monoclonal antibody (mAb) or preventing CTSS-mediated cleavage. Small-molecule inhibitors are not effective in this case.

The authors also demonstrate that blocking ARG1, combined with immune checkpoint inhibitors, can restore CD8+ T cell function in ex vivo PDAC tumors. Additionally, anti-hARG1 mAbs increase the frequency of adoptively transferred tumor-specific CD8+ T cells in tumor and enhance the effectiveness of immune checkpoint therapy in humanized mice.

Overall, the study suggests that targeting extracellular ARG1 using mAbs could be a potential therapeutic approach for treating PDAC, particularly in combination with immune checkpoint inhibitors. However, further exploration is needed to determine the clinical applicability of this approach.