Neutralization of NET-associated human ARG1 enhances cancer immunotherapy

Area of Science:

• Immunology
• Cancer Biology
• Metabolic Pathways

Background:

• Myeloid cells inhibit antitumor immunity via metabolic pathways, including l-arginine degradation by arginase 1 (ARG1).
• Arginine metabolism is crucial in pancreatic ductal adenocarcinoma (PDAC) progression, but species-specific ARG1 evolution hinders clinical translation.
• Neutrophil extracellular traps (NETs) are implicated in cancer immunity modulation.

Purpose of the Study:

• To investigate the role of extracellular arginase 1 (ARG1) in pancreatic ductal adenocarcinoma (PDAC) and its interaction with neutrophil extracellular traps (NETs).
• To explore novel therapeutic strategies targeting ARG1 for PDAC treatment by overcoming species-specific differences.

Main Methods:

• Isolation of spontaneously activated neutrophils from PDAC patients to analyze NET formation and associated enzymes.
• Characterization of human ARG1 (hARG1) cleavage by cathepsin S (CTSS) within NETs and assessment of enzymatic activity.
• Evaluation of T lymphocyte suppression by NET-associated hARG1 and restoration of proliferation using anti-hARG1 monoclonal antibodies (mAbs).
• Assessment of ARG1 blockade combined with immune checkpoint inhibitors in ex vivo PDAC tumors and humanized mouse models.

Main Results:

• Neutrophil extracellular traps (NETs) from PDAC patients create a microenvironment where cathepsin S (CTSS) enhances human ARG1 (hARG1) activity.
• NET-associated hARG1 suppresses T lymphocyte proliferation, which is restored by anti-hARG1 monoclonal antibodies (mAbs) or by preventing CTSS cleavage.
• ARG1 blockade, in combination with immune checkpoint inhibitors, restores CD8+ T cell function in PDAC tumors and enhances immunotherapy efficacy in vivo.

Conclusions:

• Extracellular ARG1 localized in NETs is processed by CTSS, leading to enhanced enzymatic activity that suppresses antitumor immunity in PDAC.
• Targeting extracellular ARG1 with monoclonal antibodies represents a promising therapeutic strategy for pancreatic ductal adenocarcinoma (PDAC).
• Combined ARG1 blockade and immune checkpoint inhibition warrants further clinical investigation for PDAC treatment.