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

Abstract

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-1α (HIF-1α) on the membrane expression of these NK cell ligands in H1339 with high and MDA-MB-231 tumor cells with low basal HIF-1α 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-1α revealed that the decreased surface expression of MICA/B under hypoxia is dependent on HIF-1α in H1339 cells with high basal HIF-1α levels. Hypoxia and HIF-1α 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-1α 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-1α.

Hypoxia-induced shedding of MICA and HIF1A-mediated immune escape of pancreatic cancer cells from NK cells: role of circ_0000977/miR-153 axis

“…HIF1A in lung cancer cells with high basal HIF1A levels [27]. In our previous study, we also demonstrated that after hypoxia-induced HIF1A upregulation and consequent sMICA upregulation, NKG2D is decreasingly located at the membrane and is increasingly present in the cytoplasm following binding to sMICA [9].…”

Genetic determinants and an epistasis ofLILRA3and HLA-B*52 in Takayasu arteritis

“…HSP6A encodes heat-shock protein 70, which is a stress-induced protein like MICB. Both are ligands of activating receptors in NK cells, and their increased expressions are associated with missing self recognition by NK cells (20) and activation of NK cells. PYK2 is a downstream molecule of activatory and inhibitory receptors in NK cells.…”

Metformin inhibits cervical cancer cell proliferation by modulating PI3K/Akt-induced major histocompatibility complex class I-related chain A gene expression

“…Under normal circumstances, HSP70 expression is relatively low; however, under the conditions of protein damage caused by heat shock and hypoxia, HSP70 protein may be regulated by the PI3K/AKT/NRF2 pathway, and its expression is increased [36,37]. A previous study has shown that HSP70 plays a synergistic role with immune cells in antitumor immunity [38]. Moreover, heat shock factor 1 (HSF-1), one of the best known activators of HSP70 expression, is also an activator of the MICA gene promoter [39].…”