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Collaboration of Heat Shock Protein 70 and Stress-induced NKG2D Ligands in the Activation of NK Cells against Tumors

[ Vol. 13 , Issue. 1 ]


Ralf Dressel*   Pages 56 - 63 ( 8 )


The stress-inducible heat shock protein 70 (HSP70) contributes to the cellular stress response that protects cells from adverse environmental conditions. HSP70 can block apoptosis and other types of cell death induced by various stimuli. In malignant cells, the expression of HSP70 is frequently elevated and some cancers even depend on HSP70 overexpression to maintain their malignant phenotype. Extracellular HSP70 in contrast, provides a danger signal to the immune system and may activate anti-tumor immune responses by cytotoxic T lymphocytes (CTL) and natural killer (NK) cells. HSP70-activated NK cells, for example, can attack tumor cells that express HSP70 at the plasma membrane. This feature of HSP70 reminds of other stress-inducible molecules including the major histocompatibility complex (MHC) class I chain-related molecules A (MICA) and B (MICB), which are ligands for activating NK receptor NK group 2, member D (NKG2D) and are induced by cellular and genotoxic stress on many tumor cells. Interestingly, the stress-inducible HSP70 and stressinducible NKG2D ligands can collaborate in tumor immunosurveillance by NK cells. HSP70-activated NK cells can also kill tumor cells that express NKG2D ligands at the plasma membrane instead of HSP70. An adaptive cellular immunotherapy with autologous HSP70-stimulated NK cells may therefore target not only tumors that express HSP70 at the plasma membrane but also those that express NKG2D ligands. Notably, an overexpression of HSP70 in tumors usually fails to protect against apoptosis executed in the granule exocytosis pathway of CTL and NK cells, making immunotherapies attractive to treat HSP70-overexpressing malignancies.


Heat shock protein 70, NKG2D ligands, NK cells, cytotoxic T lymphocytes, apoptosis, cancer, stress-induced self, tumor immunity.


Institute of Cellular and Molecular Immunology, University Medical Center Göttingen, 37099 Göttingen

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