A hypoxiainduced decrease of either MICA/B or Hsp

Authors: Daniela Schilling Fabian Tetzlaff Sarah Konrad Wei Li Gabriele Multhoff

Publish Date: 2014/08/08

Volume: 20, Issue: 1, Pages: 139-147

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Abstract

Recent findings suggest that hypoxia of the tumor microenvironment contributes to immune escape from natural killer NK cellmediated cytotoxicity Heat shock protein 70 Hsp70 and the stressregulated major histocompatibility class I chainrelated 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 hypoxiainducible factor1α HIF1α on the membrane expression of these NK cell ligands in H1339 with high and MDAMB231 tumor cells with low basal HIF1α levels and its consequences on NK cellmediated cytotoxicity We could show that a hypoxiainduced decrease in the membrane expression of MICA/B and Hsp70 on H1339 and MDAMB231 cells respectively is associated with a reduced sensitivity to NK cellmediated lysis A knockdown of HIF1α revealed that the decreased surface expression of MICA/B under hypoxia is dependent on HIF1α in H1339 cells with high basal HIF1α levels Hypoxia and HIF1α did not affect the MICA/B expression in MDAMB231 cells but reduced the Hsp70 membrane expression which in turn also impaired NK cell recognition Furthermore we could show that the hypoxiainduced decrease in membrane Hsp70 is independent of HIF1α in MDAMB231 Our data indicate that hypoxiainduced downregulation of both NK cell ligands MICA/B and Hsp70 impairs NK cellmediated cytotoxicity whereby only MICA/B appears to be regulated by HIF1αThis work was supported by the Wilhelm SanderStiftung 20120781 EUCELLEUROPE 315963 BMBF Strahlenkompetenz 02NUK007E 02NUK031B 02NUK038A Innovative Therapies 01GU0823 NSCLC 16GW0030 m4 Leading Edge Cluster 16EX1021C and the DFG Cluster of Excellence Munich Centre for Advanced Photonics MAP The research leading to these results has received funding from the Deutsche Forschungsgemeinschaft DFG under Grant Agreement Nos SFB 824/B4 INST 95/9801 FUGG and INST 411/371 FUGG irradiation devices

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