Research ArticleCancer

Myeloid cell–derived HOCl is a paracrine effector that trans-inhibits IKK/NF-κB in melanoma cells and limits early tumor progression

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Science Signaling  06 Apr 2021:
Vol. 14, Issue 677, eaax5971
DOI: 10.1126/scisignal.aax5971

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MPO mitigates melanoma

Myeloid cells such as neutrophils and macrophages generate hypochlorous acid (HOCl) through the enzymatic activity of myeloperoxidase (MPO) to kill microbes. Liu et al. found that HOCl generated by MPO in myeloid cells inhibited the early development of subcutaneous melanoma tumors by suppressing NF-κB activity in tumor cells. The authors simultaneously imaged MPO activity in myeloid cells and IκB kinase activity (the upstream activator of NF-κB) in B16F10 melanoma cells subcutaneously implanted into mice. HOCl promoted a transcriptional profile in CD8+ T cells associated with T cell activation and in B16F10 cells, suggestive of an antioxidant response. Thus, MPO in myeloid cells has antitumor effects during the early stages of melanoma growth.

Abstract

The myeloperoxidase (MPO) system of myeloid-derived cells (MDCs) is central to cellular innate immunity. Upon MDC activation, MPO is secreted into phagosomes where it catalyzes the production of hypochlorous acid (HOCl), a potent chlorinating oxidant. Here, we demonstrated that the myeloid lineage–restricted MPO-HOCl system had antitumor effects in early melanoma growth in aged mice. Orthotopic melanomas grew more slowly in immunocompetent MPO+/+ host mice compared to age-matched syngeneic MPO−/− mice. Real-time intravital tumor imaging in vivo and in cell cocultures revealed a cell-cell proximity-dependent association between MDC-derived MPO enzyme activity and blockade of ligand-induced IκBα degradation in tumor cells. HOCl directly trans-inhibited IκB kinase (IKK) activity in tumor cells, thereby decreasing nuclear factor κB (NF-κB) transcriptional activation and inducing changes in the expression of genes involved in metabolic pathways, cell cycle progression, and DNA replication. By contrast, HOCl induced transcriptional changes in CD8+ T cells related to ion transport and the MAPK and PI3K-AKT signaling pathways that are associated with T cell activation. MPO increased the circulating concentrations of the myeloid cell–attracting cytokines CXCL1 and CXCL5, enhanced local infiltration by CD8+ cytotoxic T cells, and decreased tumor growth. Overall, these data reveal a role for MDC-derived HOCl as a small-molecule paracrine signaling factor that trans-inhibits IKK in melanoma tumor cells, mediating antitumor responses during early tumor progression.

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