Abstract
Natural killer (NK) cells express receptors specific for MHC class I (MHC-I) molecules involved in "missing-self" recognition of cancer and virus-infected cells. Here we elucidate the role of MHC-I-independent NKR-P1B:Clr-b interactions in the detection of oncogenic transformation by NK cells. Ras oncogene overexpression was found to promote a real-time loss of Clr-b on mouse fibroblasts and leukemia cells, mediated in part via the Raf/MEK/ERK and PI3K pathways. Ras-driven Clr-b downregulation occurred at the level of the Clrb (Clec2d) promoter, nascent Clr-b transcripts, and cell surface Clr-b protein, in turn promoting missing-self recognition via the NKR-P1B inhibitory receptor. Both Ras- and c-Myc-mediated Clr-b loss selectively augmented cytotoxicity of oncogene-transformed leukemia cells by NKR-P1B+ NK cells in vitro and enhanced rejection by WT mice in vivo Interestingly, genetic ablation of either one (Clr-b+/-) or two Clr-b alleles (Clr-b-/-) enhanced survival of Eμ-cMyc transgenic mice in a primary lymphoma model despite preferential rejection of Clr-b-/- hematopoietic cells previously observed following adoptive transfer into naïve wild-type mice in vivo Collectively, these findings suggest that the inhibitory NKR-P1B:Clr-b axis plays a beneficial role in innate detection of oncogenic transformation via NK-cell-mediated cancer immune surveillance, in addition to a pathologic role in the immune escape of primary lymphoma cells in Eμ-cMyc mice in vivo These results provide a model for the human NKR-P1A:LLT1 system in cancer immunosurveillance in patients with lymphoma and suggest it may represent a target for immune checkpoint therapy.Significance: A mouse model shows that an MHC-independent NK-cell recognition axis enables the detection of leukemia cells, with implications for a novel immune checkpoint therapy target in human lymphoma. Cancer Res; 78(13); 3589-603. ©2018 AACR.
Highlights
Natural killer (NK) cells represent a subset of innate lymphoid cells (ILC) with the capacity to recognize and eliminate a variety of pathologic target cells, including transformed, infected, transplanted, antibody-coated, and stressed cells
As NK cells have been previously shown to be involved in the control of lymphomas in the Em-cMyc model [42], we examined the expression of other NK ligands on the primary lymphomas
NK cells have been demonstrated to be important in the recognition of cells expressing oncogenes, such as c-Myc [21, 22] and Ras [24], which are known to induce NKG2D ligands (NKG2D-L) and/or promote loss of surface MHC-I molecules [25]
Summary
Natural killer (NK) cells represent a subset of innate lymphoid cells (ILC) with the capacity to recognize and eliminate a variety of pathologic target cells, including transformed, infected, transplanted, antibody-coated, and stressed cells. The missing-self hypothesis was initially formulated on the basis of the observation that class I MHC (MHC-I)-deficient tumor cells are more efficiently recognized and eliminated by NK cells [2] This paradigm has been expanded to include both. Enforced maintenance of Clr-b ligand levels during tumor development has been postulated to play a role in immunoediting and immune escape of malignant cells in the Em-cMyc spontaneous lymphoma model, whereby this selective pressure is mitigated in Nkrp1b–/– receptor–deficient mice [15]. This prompted a study of Clr-b modulation during oncogenic transformation and immune surveillance in Clr-b–/– ligand–deficient mice
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
