Survival of the fittest: how myeloid‑derived suppressor cells survive in the inhospitable tumor microenvironment

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dc.contributor.authorOstrand‑Rosenberg, Suzanne
dc.contributor.authorBeury, Daniel W.
dc.contributor.authorParker, Katherine H.
dc.contributor.authorHorn, Lucas A.
dc.date.accessioned2019-11-15T17:04:28Z
dc.date.available2019-11-15T17:04:28Z
dc.date.issued2019-09-09
dc.description.abstractMyeloid-derived suppressor cells (MDSC) are present in most cancer patients where they are signifcant contributors to the immune suppressive tumor microenvironment (TME). The TME is a hostile locale due to defciencies in oxygen (hypoxia) and nutrients, and the presence of reactive oxygen species (ROS). The survival of tumor cells within the TME is partially governed by two mechanisms: (1) Activation of the transcription factor Nuclear Factor Erythroid-derived 2-like 2 (Nrf2) which turns on genes that attenuate oxidative stress; and (2) The presence of High Mobility Group Box Protein-1 (HMGB1), a damage-associated molecular pattern molecule (DAMP) that induces autophagy and protects against apoptosis. Because Nrf2 and HMGB1 promote tumor cell survival, we speculated that Nrf2 and HMGB1 may facilitate MDSC survival. We tested this hypothesis using Nrf2+/+ and Nrf2−/− BALB/c and C57BL/6 mice and pharmacological inhibitors of HMGB1. In vitro and in vivo studies demonstrated that Nrf2 increased the suppressive potency and quantity of tumor-infltrating MDSC by upregulating MDSC production of H₂O₂ and decreasing MDSC apoptosis. Decreased apoptosis was accompanied by a decrease in the production of MDSC, demonstrating that MDSC levels are homeostatically regulated. Pharmacological inhibition of autophagy increased MDSC apoptosis, indicating that autophagy increases MDSC half-life. Inhibition of HMGB1 also increased MDSC apoptosis and reduced MDSC autophagy. These results combined with our previous fndings that HMGB1 drives the accumulation of MDSC demonstrate that HMGB1 maintains MDSC viability by inducing autophagy. Collectively, these fndings identify Nrf2 and HMGB1 as important factors that enable MDSC to survive in the TME.en_US
dc.description.sponsorshipOriginal research described in this article was supported by US National Institutes of Health Grants R01CA84232, R01CA115880, and R01GM021248. Daniel W. Beury was partially supported by a US Department of Defense fellowship W81XWH-11-1-0115.en_US
dc.description.urihttps://link.springer.com/article/10.1007/s00262-019-02388-8en_US
dc.format.extent7 pagesen_US
dc.genrejournal articles preprintsen_US
dc.identifierdoi:10.13016/m2ds9m-afqh
dc.identifier.citationOstrand‑Rosenberg, Suzanne; Beury, Daniel W.; Parker, Katherine H.; Horn, Lucas A; Survival of the fittest: how myeloid‑derived suppressor cells survive in the inhospitable tumor microenvironment; Cancer Immunol Immunother (2019); https://doi.org/10.1007/s00262-019-02388-8en_US
dc.identifier.urihttps://doi.org/10.1007/s00262-019-02388-8
dc.identifier.urihttp://hdl.handle.net/11603/16332
dc.language.isoen_USen_US
dc.publisherSpringer Berlin Heidelbergen_US
dc.relation.isAvailableAtThe University of Maryland, Baltimore County (UMBC)
dc.relation.ispartofUMBC Biological Sciences Department Collection
dc.relation.ispartofUMBC Faculty Collection
dc.rightsThis item is likely protected under Title 17 of the U.S. Copyright Law. Unless on a Creative Commons license, for uses protected by Copyright Law, contact the copyright holder or the author.
dc.subjectMDSCen_US
dc.subjectImmune suppressionen_US
dc.subjectOxidative stressen_US
dc.subjectAutophagyen_US
dc.subjectHigh mobility group box protein 1en_US
dc.subjectHMGB1en_US
dc.titleSurvival of the fittest: how myeloid‑derived suppressor cells survive in the inhospitable tumor microenvironmenten_US
dc.typeTexten_US

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