Polyglutamine protein in tumor cells sensitizes tumor cells to natural killer cell cytolysis.

• PolyQ overexpression sensitizes tumor cells to NK cell cytolysis through inducing accumulation of misfolded proteins. • Abnormal transcriptome changes induced by polyQ protein predisposes tumor cells to death upon NK cell cytolysis. • PolyQ protein in NK cells compromises NK cell cytolytic activity through inducing an exhaustion-like status. 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. [ABSTRACT FROM AUTHOR]