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Published in: Cancer Immunology, Immunotherapy 3/2024

Open Access 01-03-2024 | Pancreatic Cancer | Research

Targeting myeloperoxidase limits myeloid cell immunosuppression enhancing immune checkpoint therapy for pancreatic cancer

Authors: Angisha Basnet, Kaitlyn M. Landreth, Remi Nohoesu, Stell P. Santiago, Werner J. Geldenhuys, Brian A. Boone, Tracy W. Liu

Published in: Cancer Immunology, Immunotherapy | Issue 3/2024

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Abstract

Pancreatic ductal adenocarcinoma is a devastating disease characterized by an extreme resistance to current therapies, including immune checkpoint therapy. The limited success of immunotherapies can be attributed to a highly immunosuppressive pancreatic cancer microenvironment characterized by an extensive infiltration of immune suppressing myeloid cells. While there are several pathways through which myeloid cells contribute to immunosuppression, one important mechanism is the increased production of reactive oxygen species. Here, we evaluated the contribution of myeloperoxidase, a myeloid-lineage restricted enzyme and primary source of reactive oxygen species, to regulate immune checkpoint therapy response in preclinical pancreatic cancer models. We compared treatment outcome, immune composition and characterized myeloid cells using wild-type, myeloperoxidase-deficient, and myeloperoxidase inhibitor treated wild-type mice using established subcutaneous pancreatic cancer models. Loss of host myeloperoxidase and pharmacological inhibition of myeloperoxidase in combination with immune checkpoint therapy significantly delayed tumor growth. The tumor microenvironment and systemic immune landscape demonstrated significant decreases in myeloid cells, exhausted T cells and T regulatory cell subsets when myeloperoxidase was deficient. Loss of myeloperoxidase in isolated myeloid cell subsets from tumor-bearing mice resulted in decreased reactive oxygen species production and T cell suppression. These data suggest that myeloperoxidase contributes to an immunosuppressive microenvironment and immune checkpoint therapy resistance where myeloperoxidase inhibitors have the potential to enhance immunotherapy response. Repurposing myeloperoxidase specific inhibitors may provide a promising therapeutic strategy to expand therapeutic options for pancreatic cancer patients to include immunotherapies.
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Metadata
Title
Targeting myeloperoxidase limits myeloid cell immunosuppression enhancing immune checkpoint therapy for pancreatic cancer
Authors
Angisha Basnet
Kaitlyn M. Landreth
Remi Nohoesu
Stell P. Santiago
Werner J. Geldenhuys
Brian A. Boone
Tracy W. Liu
Publication date
01-03-2024
Publisher
Springer Berlin Heidelberg
Published in
Cancer Immunology, Immunotherapy / Issue 3/2024
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI
https://doi.org/10.1007/s00262-024-03647-z

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