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Neutralization of NET-associated human ARG1 enhances cancer immunotherapy

S. Canè,R. Barouni,M. Fabbi,J. Cuozzo,G. Fracasso,A. Adamo,S. Ugel,R. Trovato,F. De Sanctis,M. Giacca,R. Lawlor,A. Scarpa,B. Rusev,G. Lionetto,S. Paiella,R. Salvia,C. Bassi,S. Mandruzzato,S. Ferrini,V. Bronte

Published 2023 in Science Translational Medicine

ABSTRACT

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. Description Immunosuppressive ARG1 is cleaved by CTSS to a functionally active form in NETs released by activated neutrophils of patients with PDAC. Nothing but NET for PDAC Pancreatic ductal adenocarcinoma (PDAC) is known for its immunosuppressive tumor microenvironment, in part due to arginine metabolism where the enzyme arginase 1 (ARG1) affects T cell proliferation. ARG1 is an enzyme that is evolutionarily different in mice and humans, which has so far created a translational hurdle. To overcome this, Canè et al. have shown that neutrophil extracellular traps (NETs) cleave human ARG1 (hARG1), suppressing T lymphocyte proliferation that can be restored with an hARG1 monoclonal antibody (mAb). hARG1 mAb combined with immune checkpoint inhibitors restored T cell proliferation in humanized mice and extended survival, representing a target that warrants further study. —DH

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