Research ArticleCancer

Blocking immunosuppressive neutrophils deters pY696-EZH2–driven brain metastases

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Science Translational Medicine  27 May 2020:
Vol. 12, Issue 545, eaaz5387
DOI: 10.1126/scitranslmed.aaz5387

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Closing the door to neutrophils

Brain metastasis, which occurs in many cancers, is an ominous finding that remains difficult to treat. It is challenging to get treatments into these tumors, and their microenvironment is not as well studied as that of peripheral cancers. Zhang et al. found that an epigenetic modifying protein called enhancer of zeste homolog 2 (EZH2) is overexpressed in brain metastases, where it stimulates signaling pathways recruiting immunosuppressive neutrophils into the tumors. By examining the mechanism of action of EZH2 in this setting, the authors identified two approaches for blocking this influx of neutrophils and enhancing antitumor immune responses and then demonstrated their effectiveness in multiple mouse models.

Abstract

The functions of immune cells in brain metastases are unclear because the brain has traditionally been considered “immune privileged.” However, we found that a subgroup of immunosuppressive neutrophils is recruited into the brain, enabling brain metastasis development. In brain metastatic cells, enhancer of zeste homolog 2 (EZH2) is highly expressed and phosphorylated at tyrosine-696 (pY696)–EZH2 by nuclear-localized Src tyrosine kinase. Phosphorylation of EZH2 at Y696 changes its binding preference from histone H3 to RNA polymerase II, which consequently switches EZH2’s function from a methyltransferase to a transcription factor that increases c-JUN expression. c-Jun up-regulates protumorigenic inflammatory cytokines, including granulocyte colony-stimulating factor (G-CSF), which recruits Arg1+- and PD-L1+ immunosuppressive neutrophils into the brain to drive metastasis outgrowth. G-CSF–blocking antibodies or immune checkpoint blockade therapies combined with Src inhibitors impeded brain metastasis in multiple mouse models. These findings indicate that pY696-EZH2 can function as a methyltransferase-independent transcription factor to facilitate the brain infiltration of immunosuppressive neutrophils, which could be clinically targeted for brain metastasis treatment.

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