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Translational Therapeutics

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

British Journal of Cancer volume 128, pages 331–341 (2023)Cite this article

Subjects

Abstract

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.

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Fig. 1: Orthotopic pancreatic cancer isograft mouse models characterisation.
Fig. 2: Effect of Ladarixin on tumour-mediated polarisation and migration of bone marrow-derived macrophages (BMDM).
Fig. 3: Ladarixin in vitro effect on tumour cells.
Fig. 4: Pancreatic cancer CDG mouse models.
Fig. 5: Orthotopic patient-derived xenograft (PDX) in human immune-reconstituted (HIR) mice.
Fig. 6: Gene ontology (GO) biological processes analysis in the combination treatment versus single treatment.

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Data availability

The data of this study are available from the corresponding author upon request.

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Acknowledgements

We would like to thank the Italian Pancreatic Cancer Community (IPCC, www.i-pcc.org) and “Fondazione Nadia Valsecchi Onlus” for the precious networking in the pancreatic cancer field. We would like to thank the members of the Cen.Ri.S. animal facility Mancuso A, Aquilina M and Caristo ME for their valuable assistance during in vivo experiments.

Funding

This work was supported by the AIRC IG grant number 26330 to GT; AIRC StartUp Grant No. 18178 to VC; AIRC5x1000 grant number 12182 and grant from Italian Ministry of Health FIMCUP_J38D19000690001 to AS; Ministry of Health (CO 2019‐12369662) to GT; My First AIRC Grant “Luigi Bonatti e Anna Maria Bonatti Rocca”, grant number 23681 to CC.

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Author notes

  1. These authors jointly supervised this work: Geny Piro, Carmine Carbone.

Authors and Affiliations

  1. Medical Oncology, Department of Medical and Surgical Sciences Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, Rome, Italy

    Geny Piro, Carmine Carbone, Antonio Agostini, Annachiara Esposito, Alessia Caggiano & Giampaolo Tortora

  2. Dompé Farmaceutici S.p.A., Via Santa Lucia 6, Milan, Italy

    Maria De Pizzol, Rubina Novelli, Marcello Allegretti & Andrea Aramini

  3. Division of Anatomic Pathology and Histology, Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, Rome, Italy

    Alessia Granitto & Maurizio Martini

  4. Department of Medicine, Section of Immunology, University of Verona, Verona, Italy

    Francesco De Sanctis & Stefano Ugel

  5. Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy

    Vincenzo Corbo, Rita Teresa Lawlor & Aldo Scarpa

  6. ARC-Net Research Centre, University and Hospital Trust of Verona, Verona, Italy

    Vincenzo Corbo, Rita Teresa Lawlor & Aldo Scarpa

  7. Medical Oncology, Department of Translational Medicine, Catholic University of the Sacred Heart, Rome, Italy

    Giampaolo Tortora

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  1. Geny Piro
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Contributions

CC, GP, MDP, MA, AS and GT conceived and designed the study; CC and GP designed and performed the majority of the experiments; VC provided cancer cells; FS, EAC, FDS and SU performed experiments; MM and AG performed IHC analyses; AA performed bioinformatics analyses. CC, GP AA, MDP, RN, MA, AAr, AS, VC and GT wrote the manuscript.

Corresponding author

Correspondence to Giampaolo Tortora.

Ethics declarations

Competing interests

MDP, RN, MA and AAr are employees of Dompé Farmaceutici S.p.A. The remaining authors declare no competing interests.

Ethics approval and consent to participate

In vivo experiments were conducted in accordance with the guidelines of the Institutional OPBA and the Italian Ministry of Health Ethics Committee.

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The study protocol was approved by the Institutional Board of the University of Verona, Verona, Italy. The study was conducted according to the principles of the Declaration of Helsinki and was performed in compliance with Good Clinical Practice guidelines. Written informed consent was obtained.

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Piro, G., Carbone, C., Agostini, A. et al. CXCR1/2 dual-inhibitor ladarixin reduces tumour burden and promotes immunotherapy response in pancreatic cancer. Br J Cancer 128, 331–341 (2023). https://doi.org/10.1038/s41416-022-02028-6

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