PT  - JOURNAL ARTICLE
AU  - Tracy W Liu
AU  - Seth T Gammon
AU  - Ping Yang
AU  - Wencai Ma
AU  - Jing Wang
AU  - David Piwnica-Worms
TI  - Inhibition of myeloperoxidase enhances immune checkpoint therapy for melanoma
AID  - 10.1136/jitc-2022-005837
DP  - 2023 Feb 01
TA  - Journal for ImmunoTherapy of Cancer
PG  - e005837
VI  - 11
IP  - 2
4099  - http://jitc.bmj.com/content/11/2/e005837.short
4100  - http://jitc.bmj.com/content/11/2/e005837.full
SO  - J Immunother Cancer2023 Feb 01; 11
AB  - Background The presence of a highly immunosuppressive tumor microenvironment has limited the success of immune checkpoint therapy (ICT). Immune suppressing myeloid cells with increased production of reactive oxygen species are critical drivers of this immunosuppressive tumor microenvironment. Strategies to limit these immune suppressing myeloid cells are needed to enhance response to ICT.Methods To evaluate the contribution of myeloperoxidase (MPO), a myeloid lineage-restricted enzyme and a major source of reactive oxygen species, to mediating ICT response, we compared treatment outcome and immune composition in wild-type, MPO-deficient (MPO−/−), and MPO inhibitor-treated wild-type mice using established primary melanoma models.Results Tumor growth and survival studies demonstrated that either host deficiency (MPO−/−) or pharmacological inhibition of MPO enhanced ICT response in two preclinical models of established primary melanoma in aged animals. The tumor microenvironment and systemic immune landscape underwent striking changes in infiltration of myeloid cells, T cells, B cells, and dendritic cells in MPO−/− mice; furthermore, a significant increase in myeloid cells was observed in ICT non-responders. The contribution of CD4+ T cells and NK cells during ICT response also changed in MPO−/− mice. Interestingly, MPO enzymatic activity, but not protein, was increased in CD11b+Ly6G+ myeloid cells isolated from marrow, spleen, and peritoneal cavities of mice bearing untreated melanoma, indicating systemic activation of innate immunity. Notably, repurposing MPO-specific inhibitors (verdiperstat, AZD5904) in combination with ICT pointedly enhanced response rates above ICT alone. Indeed, long-term survival was 100% in the YUMM3.3 melanoma model on treatment with verdiperstat plus ICT.Conclusion MPO contributes to ICT resistance in established melanoma. Repurposing MPO-specific inhibitors may provide a promising therapeutic strategy to enhance ICT response.Data are available in a public, open access repository. All data relevant to the study are included in the article or uploaded as online supplementary information. All data relevant to the study are included in the article, uploaded as online supplementary information or have been deposited in the public, open access repository NCBI’s Gene Expression Omnibus and are accessible through GEO Series accession number GSE215005 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE215005).