Tumor immune evasion through IRGQ-directed autophagy

The autophagy-lysosome system directs the degradation of a wide variety of cargo and is also involved in tumor progression. Here we show that immunity-related GTPase family Q protein (IRGQ) acts in the quality control of MHC-I molecules and directs misfolded MHC-I for lysosomal degradation through its binding to GABARAP-L2 and LC3B. IRGQ specifically recognizes the non-conformational heavy chains of MHC-I, sorting them for degradation through the autophagy-lysosome system. In the absence of IRGQ, MHC-I heavy chains accumulate in the cell and partly get localized to the cell surface, thereby increasing interactions with mature MHC-I molecules and promoting T cell immune responses. Accordingly, mice suffering from hepatocellular carcinoma with reduced IRGQ levels display higher survival rates and bear more activated CD8+ T cells. Conversly, low IRGQ expression in human liver cancer correlates with higher levels of MHC-I molecules in the tumors, and patient survival is directly affected by IRGQ expression levels in CD8+ enriched tumors. Moreover, human T cells are more reactive towards tumorigenic IRGQ knock-out cells. Thus, we identify IRGQ as a regulator of MHC-I quality control, mediating tumor immune evasion and marking it as a potential biomarker and therapeutic target.

自噬溶酶体系统（autophagy-lysosome system）可介导多种底物的降解，同时参与肿瘤进展过程。本研究揭示，免疫相关GTP酶家族Q蛋白（immunity-related GTPase family Q protein，IRGQ）可调控主要组织相容性复合体I类分子（MHC-I）的质量控制，并通过结合GABARAP-L2与LC3B，将错误折叠的MHC-I分子导向溶酶体降解途径。IRGQ可特异性识别MHC-I的非构象型重链，并通过自噬溶酶体系统将其分选降解。在IRGQ缺失的情况下，MHC-I重链会在细胞内蓄积，部分会定位至细胞表面，进而增加与成熟MHC-I分子的相互作用，促进T细胞免疫应答。相应地，IRGQ表达水平降低的肝细胞癌小鼠存活率更高，且肿瘤内活化CD8+ T细胞数量更多。反之，人类肝癌组织中低IRGQ表达与肿瘤内MHC-I分子高水平表达相关；且在CD8+富集的肿瘤中，患者生存率直接受IRGQ表达水平影响。此外，人类T细胞对IRGQ敲除的肿瘤细胞的反应性更强。综上，本研究鉴定IRGQ为MHC-I质量控制的调控因子，可介导肿瘤免疫逃逸，并将其标记为潜在的生物标志物与治疗靶点。