The Inhibitory NKR-P1B:Clr-b Recognition Axis Facilitates Detection of Oncogenic Transformation and Cancer Immunosurveillance.

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.