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

Abstract

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.

Keywords: Autophagy; HMGB1; High mobility group box protein 1; Immune suppression; MDSC; Oxidative stress.

Fig. 1

MDSC survival in the tumor microenvironment is facilitated by the activation of Nrf2 and by HMGB1-induced autophagy. a The TME is hypoxic, inflamed, and nutrient-deprived and includes reactive oxygen species (ROS) and high mobility group box protein 1 (HMGB1). Activation of Nrf2 in MDSC results in the production of many anti-oxidant proteins that (1) protect MDSC from oxidative stress, (2) increase the number of tumor-infiltrating MDSC, (3) facilitate MDSC survival, and (4) protect MDSC from apoptosis. HMGB1, which is ubiquitously present in the TME, increases MDSC (1) suppressive activity, (2) accumulation, (3) survival, and (4) autophagy. b Nrf2 transcriptionally regulates the autophagy-related protein p62, which is an adaptor protein that recruits ubiquitinated autophagy substrates to the autophagosome. Subsequently, p62 also interacts with KEAP1 and sequesters it away from Nrf2. Thus, activated Nrf2 not only directly protects MDSC against oxidative stress, but it also facilitates autophagy, which further facilitates MDSC survival