High-mobility group box protein 1 promotes the survival of myeloid-derived suppressor cells by inducing autophagy
High-mobility group box protein 1 promotes the survival of myeloid-derived suppressor cells by inducing autophagy
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DOI：
10.1189/jlb.3hi0715-305r
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发表时间：
2016-09-01
影响因子：
5.5
通讯作者：
Ostrand-Rosenberg, Suzanne
中科院分区：
文献类型：
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作者：
Parker, Katherine H.;Horn, Lucas A.;Ostrand-Rosenberg, Suzanne
HMGB1促进MDSC中的自噬，从而增加它们在肿瘤微环境中的存活。骨髓来源的抑制细胞是免疫抑制细胞，在大多数癌症患者中升高，其中它们的积累和抑制活性由炎症驱动。由于骨髓来源的抑制细胞抑制抗肿瘤免疫并促进肿瘤进展，我们正在确定它们的活力是如何调节的。先前的研究已经确定，损伤相关的分子模式分子高迁移率族蛋白1驱动髓源性抑制细胞积累和抑制效力，并且普遍存在于肿瘤微环境中。由于高迁移率族蛋白1也通过诱导自噬促进肿瘤细胞存活，我们试图确定高迁移率族蛋白1是否通过诱导自噬调节髓源性抑制细胞存活。自噬的抑制增加了凋亡的髓源性抑制细胞的数量，表明自噬延长了髓源性抑制细胞的存活并增加了其活力。高迁移率族蛋白1的抑制类似地增加了凋亡的髓源性抑制细胞的水平，并减少了髓源性抑制细胞自噬，这表明除了诱导髓源性抑制细胞的积累之外，高迁移率族蛋白1还维持了髓源性抑制细胞的活力。循环的髓源性抑制细胞具有默认的自噬表型，并且肿瘤浸润的髓源性抑制细胞更具自噬性，这与实体瘤微环境内的炎症和缺氧条件通过增强免疫抑制性髓源性抑制细胞而促进肿瘤进展的概念一致。总的来说，这些结果表明，除了以前认识到的促肿瘤作用，高迁移率族蛋白1有助于通过增加骨髓来源的抑制细胞的活力，通过驱动它们进入proautophagic状态的肿瘤进展。
HMGB1 promotes autophagy in MDSC, thereby increasing their survival in the tumor microenvironment. 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.