The Receptor for Advanced Glycation Endproducts (RAGE) and Its Ligands S100A8/A9 and High Mobility Group Box Protein 1 (HMGB1) Are Key Regulators of Myeloid-Derived Suppressor Cells

SIMPLE SUMMARY: Cancer immunotherapies using antibodies and genetically modified T cells are effective in a subset of cancer patients. However, many cancer patients do not respond to immunotherapy because their cancers induce cells called myeloid-derived suppressor cells (MDSCs) that antagonize the immune system. Clinical and animal studies indicate that non-responding cancer patients have elevated levels of MDSCs. Therefore, a better understanding of the mechanisms that drive the accumulation and function of MDSCs may lead to improved cancer therapies. This article summarizes the role of an important receptor (RAGE: receptor for advanced glycation endproducts) and its two dominant ligands (S100A8/A9 and high mobility group box protein 1 (HMGB1)) that induce the accumulation and increase the immune suppressive function of MDSCs. S100A8/A9 and HMGB1 are potential biomarkers for the accumulation of MDSCs and their neutralization and/or the inhibition of RAGE may enhance cancer immunotherapies. ABSTRACT: Immunotherapies including checkpoint blockade immunotherapy (CBI) and chimeric antigen receptor T cells (CAR-T) have revolutionized cancer treatment for patients with certain cancers. However, these treatments are not effective for all cancers, and even for those cancers that do respond, not all patients benefit. Most cancer patients have elevated levels of myeloid-derived suppressor cells (MDSCs) that are potent inhibitors of antitumor immunity, and clinical and animal studies have demonstrated that neutralization of MDSCs may restore immune reactivity and enhance CBI and CAR-T immunotherapies. MDSCs are homeostatically regulated in that elimination of mature circulating and intratumoral MDSCs results in increased production of MDSCs from bone marrow progenitor cells. Therefore, targeting MDSC development may provide therapeutic benefit. The pro-inflammatory molecules S100A8/A9 and high mobility group box protein 1 (HMGB1) and their receptor RAGE are strongly associated with the initiation and progression of most cancers. This article summarizes the literature demonstrating that these molecules are integrally involved in the early development, accumulation, and suppressive activity of MDSCs, and postulates that S100A8/A9 and HMGB1 serve as early biomarkers of disease and in conjunction with RAGE are potential targets for reducing MDSC levels and enhancing CBI and CAR-T immunotherapies.