Inhibition of myeloperoxidase enhances immune checkpoint therapy for melanoma

Abstract

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.