Survival of the fittest: how myeloid-derived suppressor cells survive in the inhospitable tumor microenvironment
Myeloid-derived suppressor cells (MDSC) are present in most cancer patients where they are significant contributors to the immune suppressive tumor microenvironment (TME). The TME is a hostile locale due to deficiencies 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-infiltrating MDSC by up-regulating 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 findings that HMGB1 drives the accumulation of MDSC demonstrate that HMGB1 maintains MDSC viability by inducing autophagy. Collectively, these findings identify Nrf2 and HMGB1 as important factors that enable MDSC to survive in the TME.
KeywordsMDSC Immune suppression Oxidative stress Autophagy High mobility group box protein 1 HMGB1
Anti-oxidant response elements
Checkpoint blockade inhibitors
Cytotoxic T-lymphocyte-associated protein 4
Damage-associated molecular pattern
High mobility group box protein 1
Kelch-like ECH-associated protein 1
Myeloid-derived suppressor cells
Mammalian target of rapamycin
Nuclear factor erythroid-2-related factor 2
Programmed cell death protein 1
Programmed death-ligand 1
Polymorphonuclear or granulocytic MDSC
Receptor for advanced glycation endproducts
Reactive oxygen species
The authors thank Ms. Virginia Clements for her outstanding technical support, and the undergraduate students at UMBC who participated in some of the original studies.
DWB, KHP, and LAH performed experiments. All authors developed the concepts, designed experiments, analyzed data, and wrote and edited the manuscript.
Original 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.
Compliance with ethical standards
Conflict of interest
The authors declare they have no conflict of interest.
Research involving animals
Original research described in this article was approved by the UMBC Institutional Animal Care and Use Committee, protocol #SO01691417.
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