Ostrand-Rosenberg Suzanne, Huecksteadt Tom, Sanders Karl
Department of Pathology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, UT 84148, USA.
Cancers (Basel). 2023 Feb 6;15(4):1026. doi: 10.3390/cancers15041026.
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.
免疫疗法，包括检查点阻断免疫疗法（CBI）和嵌合抗原受体T细胞（CAR-T），已经彻底改变了某些癌症患者的癌症治疗方式。然而，这些治疗方法并非对所有癌症都有效，甚至对于那些有反应的癌症，也并非所有患者都能从中受益。大多数癌症患者的髓源性抑制细胞（MDSC）水平升高，而MDSC是抗肿瘤免疫的强效抑制剂，临床和动物研究表明，中和MDSC可能恢复免疫反应性并增强CBI和CAR-T免疫疗法。MDSC受到稳态调节，即消除成熟的循环和肿瘤内MDSC会导致骨髓祖细胞产生更多的MDSC。因此，靶向MDSC的发育可能会带来治疗益处。促炎分子S100A8/A9和高迁移率族蛋白1（HMGB1）及其受体RAGE与大多数癌症的发生和发展密切相关。本文总结了相关文献，表明这些分子在MDSC的早期发育、积累和抑制活性中起着不可或缺的作用，并推测S100A8/A9和HMGB1作为疾病的早期生物标志物，与RAGE一起是降低MDSC水平以及增强CBI和CAR-T免疫疗法的潜在靶点。
