Myeloid-Derived Suppressor Cell Survival and Function Are Regulated by the Transcription Factor Nrf2
Links to Fileshttp://www.jimmunol.org/content/196/8/3470.long
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Type of Work10 pages
Citation of Original PublicationDaniel W. Beury, Kayla A. Carter, Cassandra Nelson, Pratima Sinha, Erica Hanson, Maeva Nyandjo, Phillip J. Fitzgerald, Amry Majeed, Neha Wali and Suzanne Ostrand-Rosenberg, Myeloid-Derived Suppressor Cell Survival and Function Are Regulated by the Transcription Factor Nrf2, J Immunol April 15, 2016, 196 (8) 3470-3478, DOI: https://doi.org/10.4049/jimmunol.1501785
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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. Nuclear factor erythroid derived 2-like 2 (Nrf2) is a transcription factor that regulates a battery of genes which attenuates oxidative stress. Therefore, we hypothesized that MDSC resistance to ROS may be regulated by Nrf2. To test this hypothesis, we utilized 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 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 since 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.