Extracellular heat‐shock protein 90 down‐regulates NK cell immune responses

Abstract

90‐Kda heat‐shock proteins (Hsp90s) are expressed on various cells. The function of Hsp90 is different depending on the intracellular and extracellular locations. Intracellular Hsp90 has protective function regulating programmed cell death in lethal condition and thereby blocks the apoptotic cell death. Cancer cells abnormally express a high level of Hsp90 and intracellularly overexpressed Hsp90 facilitates oncogenesis and chemotherapy resistance. In contrast, extracellular Hsp90 or membrane‐bound Hsp90 is related to immune responses but the function of extracellular Hsp90 is not known well. NK cells are cytotoxic lymphocytes that play an important role in the rejection of tumor and virus infected cells. Here we showed the effects of the extracellular Hsp90 to NK cells. We investigated interferon‐γ (IFN‐γ) secretion, cytotoxic effects, and the changes of various receptors and ligands expression of NK cells when treated with recombinant Hsp90 with/without IL‐2. As a result, the recombinant Hsp90 was not effective in IFN‐γ secretion but it inhibited IFN‐γ secretion of IL‐2 stimulated NK cells. In addition, NK cell cytotoxicity to breast and ovarian cancer cell lines, MCF7 and CAOV3, was inhibited when NK cells were treated with Hsp90. Consistently with the above results, the recombinant Hsp90 down regulated TRAIL, NKG2D, and HLA‐DR and up regulated inhibitory receptor KIR. These results demonstrated that the extracellular Hsp90 down‐regulates NK cell immune responses, therefore, blocking the intracellular and extracellular Hsp90 can be helpful in preventing cancer progression and in enhancing immune responses against the cancer cells.