Patients with Huntington’s diseases display reduced tumor incidence mediated by unclear mechanisms. Besides, the effects of characteristic overexpression of 97 polyglutamine protein (polyQ protein) on tumor surveillance by the host immune system have not been investigated. NK cells are cytotoxic innate lymphocytes that sense and kill stressed and transformed cells through recognition of abnormal molecular patterns. Here, we found that polyQ protein induced the accumulation of misfolded proteins in tumor cells and sensitized these tumor cells to NK cell cytolysis in vitro. Transcriptome analysis showed that polyQ protein overexpression caused an abnormal transcriptome changes in tumor cells, which might predispose these tumor cells to death upon NK cell cytolysis. However, on the other hand, polyQ protein in NK cells compromised NK cell cytolytic activity through forcing the accumulation of misfolded proteins. Furthermore, polyQ overexpression enriched oxidative phosphorylation related gene set in NK cells, which might lead to an exhaustion-like status of NK cells with reduced cytolytic activity. Therefore, our study shows that polyQ protein overexpression in tumors alone, but not in both tumor cells and NK cells, might result in increased tumor rejection by NK cells, revealing a dual role of polyQ protein on tumor surveillance by the immune system.

亨廷顿舞蹈病患者因机制不明而导致肿瘤发生率降低。此外，还没有研究过特征性的97聚谷氨酰胺蛋白（polyQ蛋白）的过表达对宿主免疫系统监视肿瘤的影响。NK细胞是细胞毒性先天性淋巴细胞，可通过识别异常分子模式来感知并杀死受压和转化的细胞。在这里，我们发现polyQ蛋白诱导错误折叠的蛋白在肿瘤细胞中的积累，并使这些肿瘤细胞在体外对NK细胞的细胞溶解敏感。转录组分析表明polyQ蛋白的过表达导致肿瘤细胞中异常的转录组变化，这可能使这些肿瘤细胞在NK细胞溶细胞时死亡。但是，另一方面 NK细胞中的polyQ蛋白通过迫使错误折叠的蛋白积累而损害了NK细胞的细胞溶解活性。此外，polyQ过表达富集了NK细胞中与氧化磷酸化相关的基因集，这可能导致NK细胞的精疲力尽，细胞溶解活性降低。因此，我们的研究表明，仅在肿瘤中而不在肿瘤细胞和NK细胞中都表达过polyQ蛋白，可能会导致NK细胞对肿瘤的排斥反应增加，从而揭示了polyQ蛋白在免疫系统监测肿瘤中的双重作用。