title: Myeloid-Derived Suppressor Cell Survival and Function Are Regulated by the Transcription Factor Nrf2.
abstract: Tumor-induced myeloid-derived suppressor cells (MDSC) contribute to immune suppression in tumor-bearing individuals and are a major obstacle to effective immunotherapy. Reactive oxygen species (ROS) are one of the mechanisms used by MDSC to suppress T cell activation. Although ROS are toxic to most cells, MDSC survive despite their elevated content and release of ROS. NF erythroid 2-related factor 2 (Nrf2) is a transcription factor that regulates a battery of genes that attenuate oxidative stress. Therefore, we hypothesized that MDSC resistance to ROS may be regulated by Nrf2. To test this hypothesis, we used Nrf2(+/+)and Nrf2(-/-)BALB/c and C57BL/6 mice bearing 4T1 mammary carcinoma and MC38 colon carcinoma, respectively. Nrf2 enhanced MDSC suppressive activity by increasing MDSC production of H2O2, and it increased the quantity of tumor-infiltrating MDSC by reducing their oxidative stress and rate of apoptosis. Nrf2 did not affect circulating levels of MDSC in tumor-bearing mice because the decreased apoptotic rate of tumor-infiltrating MDSC was balanced by a decreased rate of differentiation from bone marrow progenitor cells. These results demonstrate that Nrf2 regulates the generation, survival, and suppressive potency of MDSC, and that a feedback homeostatic mechanism maintains a steady-state level of circulating MDSC in tumor-bearing individuals.
authors.affiliation: Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD 21250.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Beury
authors.affiliation: Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD 21250.
authors.forename: Kayla A
authors.initials: KA
authors.lastname: Carter
authors.affiliation: Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD 21250.
authors.forename: Cassandra
authors.initials: C
authors.lastname: Nelson
authors.affiliation: Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD 21250.
authors.forename: Pratima
authors.initials: P
authors.lastname: Sinha
authors.affiliation: Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD 21250.
authors.forename: Erica
authors.identifier: http://orcid.org/0000-0003-3261-0025
authors.initials: E
authors.lastname: Hanson
authors.affiliation: Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD 21250.
authors.forename: Maeva
authors.initials: M
authors.lastname: Nyandjo
authors.affiliation: Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD 21250.
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Fitzgerald
authors.affiliation: Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD 21250.
authors.forename: Amry
authors.initials: A
authors.lastname: Majeed
authors.affiliation: Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD 21250.
authors.forename: Neha
authors.initials: N
authors.lastname: Wali
authors.affiliation: Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD 21250 srosenbe@umbc.edu.
authors.forename: Suzanne
authors.identifier: http://orcid.org/0000-0002-2095-9732
authors.initials: S
authors.lastname: Ostrand-Rosenberg
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation / Q000276:immunology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000276:immunology; D003110:Colonic Neoplasms / Q000473:pathology; D005260:Female; D006861:Hydrogen Peroxide / Q000378:metabolism; D007108:Immune Tolerance / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D015674:Mammary Neoplasms, Animal / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000166:cytology* / Q000276:immunology; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D018384:Oxidative Stress / Q000235:genetics; D013234:Stem Cells / Q000166:cytology; D019139:Tumor Escape / Q000276:immunology*
chemical_list: D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D006861:Hydrogen Peroxide