| Autor: |
Canè S; Department of Medicine, Section of Immunology, University of Verona, Verona 37129, Italy., Barouni RM; Department of Medicine, Section of Immunology, University of Verona, Verona 37129, Italy., Fabbi M; Ospedale Policlinico San Martino, IRCCS, Genova16132, Italy., Cuozzo J; ZebiAI Therapeutics Inc., Waltham, MA 02467, USA., Fracasso G; Department of Medicine, Section of Immunology, University of Verona, Verona 37129, Italy., Adamo A; Department of Medicine, Section of Immunology, University of Verona, Verona 37129, Italy., Ugel S; Department of Medicine, Section of Immunology, University of Verona, Verona 37129, Italy., Trovato R; Department of Medicine, Section of Immunology, University of Verona, Verona 37129, Italy., De Sanctis F; Department of Medicine, Section of Immunology, University of Verona, Verona 37129, Italy., Giacca M; King's College, London WC2R 2LS, UK., Lawlor R; ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona 37134, Italy., Scarpa A; ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona 37134, Italy.; Department of Diagnostic and Public Health, University of Verona, Verona 37134, Italy., Rusev B; ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona 37134, Italy.; Department of Diagnostic and Public Health, University of Verona, Verona 37134, Italy., Lionetto G; General and Pancreatic Surgery, Pancreas Institute, University of Verona, Verona 37134, Italy., Paiella S; General and Pancreatic Surgery, Pancreas Institute, University of Verona, Verona 37134, Italy., Salvia R; General and Pancreatic Surgery, Pancreas Institute, University of Verona, Verona 37134, Italy., Bassi C; General and Pancreatic Surgery, Pancreas Institute, University of Verona, Verona 37134, Italy., Mandruzzato S; Dipartimento di Scienze Chirurgiche Oncologiche e Gastroenterologiche, University of Padova, Padova 35122, Italy.; Istituto Oncologico Veneto IRCCS, Padova 35128, Italy., Ferrini S; Ospedale Policlinico San Martino, IRCCS, Genova16132, Italy., Bronte V; Istituto Oncologico Veneto IRCCS, Padova 35128, Italy. |
| Abstrakt: |
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. |
