Autophagy orchestrates the regulatory program of tumor-associated myeloid-derived suppressor cells
Autophagy orchestrates the regulatory program of tumor-associated myeloid-derived suppressor cells
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DOI：
10.1172/jci120888
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发表时间：
2018-08-31
影响因子：
15.9
通讯作者：
Verginis, Panayotis
中科院分区：
文献类型：
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作者：
Alissafi, Themis;Hatzioannou, Aikaterini;Verginis, Panayotis
骨髓源性抑制细胞（MDSC）密集地积聚在肿瘤中，并有效地抑制抗肿瘤免疫反应，促进肿瘤的发展。在肿瘤免疫治疗中靶向MDSC由于缺乏对控制MDSC分化和功能的分子途径的理解而受到阻碍。在此，我们确定自噬是MDSC介导的抗肿瘤免疫抑制的关键途径。具体而言，患有黑素瘤和小鼠黑素瘤的患者中的MDSC表现出增加的功能性自噬水平。消除骨髓细胞中的自噬显著延迟肿瘤生长并赋予抗肿瘤免疫应答。值得注意的是，肿瘤浸润性自噬缺陷型单核细胞MDSC（M-MDSC）在体外和体内表现出受损的抑制活性，而转录组分析显示与溶酶体功能相关的基因存在实质性差异。因此，自噬缺陷的M-MDSC表现出受损的溶酶体降解，从而增强MHC II类分子的表面表达，导致肿瘤特异性CD 4（+）T细胞的有效活化。最后，靶向介导M-MDSC中MHC II的溶酶体降解的膜相关RING-CH 1（MARCH 1）E3泛素连接酶减弱了它们的抑制功能，并导致肿瘤体积显著减小，随后产生强大的抗肿瘤免疫力。总的来说，这些发现将自噬描述为MDSC介导的抗肿瘤免疫抑制的分子靶点。
Myeloid-derived suppressor cells (MDSCs) densely accumulate into tumors and potently suppress antitumor immune responses, promoting tumor development. Targeting MDSCs in tumor immunotherapy has been hampered by lack of understanding of the molecular pathways that govern MDSC differentiation and function. Herein, we identify autophagy as a crucial pathway for MDSC-mediated suppression of antitumor immunity. Specifically, MDSCs in patients with melanoma and mouse melanoma exhibited increased levels of functional autophagy. Ablation of autophagy in myeloid cells markedly delayed tumor growth and endowed antitumor immune responses. Notably, tumor-infiltrating autophagy-deficient monocytic MDSCs (M-MDSCs) demonstrated impaired suppressive activity in vitro and in vivo, whereas transcriptome analysis revealed substantial differences in genes related to lysosomal function. Accordingly, autophagy-deficient M-MDSCs exhibited impaired lysosomal degradation, thereby enhancing surface expression of MHC class II molecules, resulting in efficient activation of tumor-specific CD4(+) T cells. Finally, targeting of the membrane-associated RING-CH1 (MARCH1) E3 ubiquitin ligase that mediates the lysosomal degradation of MHC II in M-MDSCs attenuated their suppressive function, and resulted in markedly decreased tumor volume followed by development of a robust antitumor immunity. Collectively, these findings depict autophagy as a molecular target of MDSC-mediated suppression of antitumor immunity.