CXCR1/2 dual-inhibitor ladarixin reduces tumour burden and promotes immunotherapy response in pancreatic cancer.

Autor: Piro G; Medical Oncology, Department of Medical and Surgical Sciences Fondazione Policlinico Universitario 'Agostino Gemelli' IRCCS, Rome, Italy., Carbone C; Medical Oncology, Department of Medical and Surgical Sciences Fondazione Policlinico Universitario 'Agostino Gemelli' IRCCS, Rome, Italy., Agostini A; Medical Oncology, Department of Medical and Surgical Sciences Fondazione Policlinico Universitario 'Agostino Gemelli' IRCCS, Rome, Italy., Esposito A; Medical Oncology, Department of Medical and Surgical Sciences Fondazione Policlinico Universitario 'Agostino Gemelli' IRCCS, Rome, Italy., De Pizzol M; Dompé Farmaceutici S.p.A., Via Santa Lucia 6, Milan, Italy., Novelli R; Dompé Farmaceutici S.p.A., Via Santa Lucia 6, Milan, Italy., Allegretti M; Dompé Farmaceutici S.p.A., Via Santa Lucia 6, Milan, Italy., Aramini A; Dompé Farmaceutici S.p.A., Via Santa Lucia 6, Milan, Italy., Caggiano A; Medical Oncology, Department of Medical and Surgical Sciences Fondazione Policlinico Universitario 'Agostino Gemelli' IRCCS, Rome, Italy., Granitto A; Division of Anatomic Pathology and Histology, Fondazione Policlinico Universitario 'Agostino Gemelli' IRCCS, Rome, Italy., De Sanctis F; Department of Medicine, Section of Immunology, University of Verona, Verona, Italy., Ugel S; Department of Medicine, Section of Immunology, University of Verona, Verona, Italy., Corbo V; Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy.; ARC-Net Research Centre, University and Hospital Trust of Verona, Verona, Italy., Martini M; Division of Anatomic Pathology and Histology, Fondazione Policlinico Universitario 'Agostino Gemelli' IRCCS, Rome, Italy., Lawlor RT; Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy.; ARC-Net Research Centre, University and Hospital Trust of Verona, Verona, Italy., Scarpa A; Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy.; ARC-Net Research Centre, University and Hospital Trust of Verona, Verona, Italy., Tortora G; Medical Oncology, Department of Medical and Surgical Sciences Fondazione Policlinico Universitario 'Agostino Gemelli' IRCCS, Rome, Italy. giampaolo.tortora@policlinicogemelli.it.; Medical Oncology, Department of Translational Medicine, Catholic University of the Sacred Heart, Rome, Italy. giampaolo.tortora@policlinicogemelli.it.
Jazyk: angličtina
Zdroj: British journal of cancer [Br J Cancer] 2023 Jan; Vol. 128 (2), pp. 331-341. Date of Electronic Publication: 2022 Nov 16.
DOI: 10.1038/s41416-022-02028-6
Abstrakt: Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with few therapeutic options available. Despite immunotherapy has revolutionised cancer treatment, the results obtained in PDAC are still disappointing. Emerging evidence suggests that chemokines/CXCRs-axis plays a pivotal role in immune tumour microenvironment modulation, which may influence immunotherapy responsiveness. Here, we evaluated the effectiveness of CXCR1/2 inhibitor ladarixin, alone or in combination with anti-PD-1, against immunosuppression in PDAC.
Methods: A set of preclinical models was obtained by engrafting mouse PDAC-derived cells into syngeneic immune-competent mice, as well as by orthotopically transplanting patient-derived PDAC tumour into human immune-system-reconstituted (HIR) mice (HuCD34-NSG-mice). Tumour-bearing mice were randomly assigned to receive vehicles, ladarixin, anti-PD-1 or drugs combination.
Results: CXCR1/2 inhibition by ladarixin reverted in vitro tumour-mediated M2 macrophages polarisation and migration. Ladarixin as single agent reduced tumour burden in cancer-derived graft (CDG) models with high-immunogenic potential and increased the efficacy of ICI in non-immunogenic CDG-resistant models. In a HIR mouse model bearing the immunogenic subtype of human PDAC, ladarixin showed high efficacy increasing the antitumor effect of anti-PD-1.
Conclusion: Ladarixin in combination with anti-PD-1 might represent an extremely effective approach for the treatment of immunotherapy refractory PDAC, allowing pro-tumoral to immune-permissive microenvironment conversion.
(© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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