Chemotherapy-Induced Genotoxic Stress Promotes Sensitivity to Natural Killer Cell Cytotoxicity by Enabling Missing-Self Recognition

• Published in: Cancer research (Chicago, Ill.) Vol. 70; no. 18; pp. 7102 - 7113
• Main Authors: FINE, Jason H, CHEN, Peter, MESCI, Aruz, ALLAN, David S. J, GASSER, Stephan, RAULET, David H, CARLYLE, James R
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.09.2010
• Subjects: Animals; Antineoplastic agents; Aphidicolin - pharmacology; Ataxia Telangiectasia Mutated Proteins; Biological and medical sciences; Bleomycin - pharmacology; Cell Cycle Proteins - metabolism; Cisplatin - pharmacology; DNA Damage - drug effects; DNA Damage - immunology; DNA-Binding Proteins - metabolism; Down-Regulation; Killer Cells, Natural - drug effects; Killer Cells, Natural - immunology; Lectins, C-Type - biosynthesis; Lectins, C-Type - immunology; Medical sciences; Membrane Proteins - biosynthesis; Membrane Proteins - immunology; Mice; NIH 3T3 Cells; Pharmacology. Drug treatments; Protein-Serine-Threonine Kinases - metabolism; Purines - pharmacology; Receptors, Immunologic - immunology; Tumor Suppressor Proteins - metabolism; Tumors; Natural killer cell; Chemotherapy; Sensitivity; Treatment; Toxicity; Genotoxicity; Cytotoxicity; Recognition; Stress
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-10-1316

Natural killer (NK) cells can recognize and kill tumor cells lacking "self" markers, such as class I MHC, but the basis for this recognition is not completely understood. NKR-P1 receptors are members of the C-type lectin-related NK receptor superfamily that are conserved from rodents to humans. Identification of Clr ligands for the NKR-P1 receptors has facilitated functional analysis of MHC-independent target cell recognition by NK cells. One receptor-ligand pair, NKR-P1B:Clr-b, can mediate "missing-self" recognition of tumor and infected cells, but the role of this axis in sensing stressed cells remains unknown. Here, we show that Clr-b is rapidly downregulated in cells undergoing genotoxic and cellular stress at the level of both RNA and surface protein. Stress-mediated loss of Clr-b on leukemia cells enhanced cytotoxicity mediated by NKR-P1B(+) NK cells. Notably, Clr-b downregulation was coordinated functionally with stress-mediated upregulation of NKG2D ligands (but not class I MHC). Our findings highlight a unique role for the MHC-independent NKR-P1B:Clr-b missing-self axis in recognition of stressed cells, and provide evidence of two independent levels of Clr-b regulation in stressed cells.