NK Cell Mediated Tumor Cytotoxicity is enhanced by Mild Thermal Stress through Heat Shock Factor 1 (50.24)

Abstract

Abstract Natural killer (NK) cells directly kill tumor cells and regulate downstream adaptive immune responses. Previous studies in our lab suggest that mild thermal stress (39.5 C) significantly enhances the cytotoxicity of human peripheral blood NK cells compared to normothermic conditions (37 C) against human colon tumor cells. This enhancement was not seen when syngeneic human PBMC were used as targets, nor when the IL-2 dependent human NK cell lines NKL or NK92MI, or IL-2 activated primary NK cells were used as effectors. Thus, we hypothesized that resting NK cell cytotoxic activity is regulated by mild thermal stress. Blocking of the activating receptor NKG2D and its stress-induced ligand MICA with blocking antibodies suggested the involvement of these molecules in the thermal regulation of NK cytotoxicity. We found that inhibitory receptor KIR2DL1 levels on NK cells were not changed with thermal stress. Increased clustering of NKG2D on NK cells was observed with thermal stress, suggesting the potential for enhanced efficiency of activating signals. However prevention of lipid raft clustering with methyl B-cyclodextrin on NK cells shows no significant affect on thermally enhanced cytotoxicity. On target cells, MICA expression appeared to be upregulated by mild thermal stress in a manner that is dependent on the transcription factor HSF-1. Overall, these data suggest that thermal therapy might be clinically utilized to help enhance NK mediated tumor cell killing. Supported by NIH P01 CA94045, R01 CA71599, Komen Foundation DISS0402487 and Fulbright Program.