title: High-mobility group box protein 1 promotes the survival of myeloid-derived suppressor cells by inducing autophagy.
abstract: Myeloid-derived suppressor cells are immune-suppressive cells that are elevated in most individuals with cancer, where their accumulation and suppressive activity are driven by inflammation. As myeloid-derived suppressor cells inhibit anti-tumor immunity and promote tumor progression, we are determining how their viability is regulated. Previous studies have established that the damage-associated molecular pattern molecule high-mobility group box protein 1 drives myeloid-derived suppressor cell accumulation and suppressive potency and is ubiquitously present in the tumor microenvironment. As high-mobility group box protein 1 also facilitates tumor cell survival by inducing autophagy, we sought to determine if high-mobility group box protein 1 regulates myeloid-derived suppressor cell survival through induction of autophagy. Inhibition of autophagy increased the quantity of apoptotic myeloid-derived suppressor cells, demonstrating that autophagy extends the survival and increases the viability of myeloid-derived suppressor cells. Inhibition of high-mobility group box protein 1 similarly increased the level of apoptotic myeloid-derived suppressor cells and reduced myeloid-derived suppressor cell autophagy, demonstrating that in addition to inducing the accumulation of myeloid-derived suppressor cells, high-mobility group box protein 1 sustains myeloid-derived suppressor cell viability. Circulating myeloid-derived suppressor cells have a default autophagic phenotype, and tumor-infiltrating myeloid-derived suppressor cells are more autophagic, consistent with the concept that inflammatory and hypoxic conditions within the microenvironment of solid tumors contribute to tumor progression by enhancing immune-suppressive myeloid-derived suppressor cells. Overall, these results demonstrate that in addition to previously recognized protumor effects, high-mobility group box protein 1 contributes to tumor progression by increasing myeloid-derived suppressor cell viability by driving them into a proautophagic state.
authors: Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, Maryland, USA.
authors: Katherine H
authors: KH
authors: Parker
authors: Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, Maryland, USA.
authors: Lucas A
authors: LA
authors: Horn
authors: Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, Maryland, USA srosenbe@umbc.edu.
authors: Suzanne
authors: S
authors: Ostrand-Rosenberg
mesh_terms: D000818:Animals; D001343:Autophagy / Q000276:immunology*; D002470:Cell Survival; D005260:Female; D024243:HMGB1 Protein / Q000502:physiology*; D007165:Immunosuppression Therapy; D007249:Inflammation / Q000276:immunology*; D008213:Lymphocyte Activation; D008325:Mammary Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D000072737:Myeloid-Derived Suppressor Cells / Q000276:immunology*; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000276:immunology*
chemical_list: D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse
keywords: DAMPs; tumor microenvironment; tumor-induced immune suppression