A hypoxia-induced decrease of either MICA/B or Hsp70 on the membrane of tumor cells mediates immune escape from NK cells

作者：Schilling, Daniela; Tetzlaff, Fabian; Konrad, Sarah; Li, Wei; Multhoff, Gabriele^*

来源：Cell Stress & Chaperones, 2015, 20(1): 139-147.

DOI：10.1007/s12192-014-0532-5

• Hsp70
• MICA/B
• Hypoxia
• HIF-1 alpha
• NK cell
• Immune escape

Recent findings suggest that hypoxia of the tumor microenvironment contributes to immune escape from natural killer (NK) cell-mediated cytotoxicity. Heat shock protein 70 (Hsp70) and the stress-regulated major histocompatibility class I chain-related protein A and B (MICA/B) both serve as ligands for activated NK cells when expressed on the cell surface of tumor cells. Herein, we studied the effects of hypoxia and hypoxia-inducible factor-1 alpha (HIF-1 alpha) on the membrane expression of these NK cell ligands in H1339 with high and MDA-MB-231 tumor cells with low basal HIF-1 alpha levels and its consequences on NK cell-mediated cytotoxicity. We could show that a hypoxia-induced decrease in the membrane expression of MICA/B and Hsp70 on H1339 and MDA-MB-231 cells, respectively, is associated with a reduced sensitivity to NK cell-mediated lysis. A knockdown of HIF-1 alpha revealed that the decreased surface expression of MICA/B under hypoxia is dependent on HIF-1 alpha in H1339 cells with high basal HIF-1 alpha levels. Hypoxia and HIF-1 alpha did not affect the MICA/B expression in MDA-MB-231 cells but reduced the Hsp70 membrane expression which in turn also impaired NK cell recognition. Furthermore, we could show that the hypoxia-induced decrease in membrane Hsp70 is independent of HIF-1 alpha in MDA-MB-231. Our data indicate that hypoxia-induced downregulation of both NK cell ligands MICA/B and Hsp70 impairs NK cell-mediated cytotoxicity, whereby only MICA/B appears to be regulated by HIF-1 alpha.

• 出版日期2015-1