Ras-mediated missing-self recognition via NKR-P1B:Clr-b interactions facilitates detection of oncogenic transformation and cancer immunosurveillance

Abstract

Abstract Natural killer (NK) cells are involved in tumor immune surveillance, immunity to infection, and various pathological conditions. One mode of NK cell recognition, ‘missing-self’ recognition, is triggered by downregulation of inhibitory self ligands on target cells, thereby decreasing the net signaling threshold to promote NK cell activation. Clr-b, ligand for the NKR-P1B inhibitory NK receptor, is downregulated during cellular transformation, viral infection, and genotoxic stress, in turn promoting MHC-independent missing-self recognition. However, the mechanisms underlying the loss of Clr-b during oncogenic transformation remain unknown. Here, we demonstrate that proto-oncogene, Ras, is directly involved in Clr-b downregulation on mouse fibroblasts via the Raf/MEK/ERK and PI3K pathways. We show that c-myc overexpression also promotes Clr-b downregulation. To examine a link between the loss of Clr-b and tumour progression using a spontaneous B cell lymphoma model, we backcrossed the Emu-c-myc transgene onto a Clr-b−/− background, then assessed the survival rates of transgenic littermates. Preliminary results reveal a trend towards accelerated tumor progression of Clr-b+/+ littermates versus Clr-b+/− littermates, suggesting a potential protective role for Clr-b loss in tumour immune surveillance, one revealed under loss-of-heterozygosity conditions. Notably, previous results using Nkrp1b−/− mice also suggest that NKR-P1B-mediated inhibition may also facilitate deleterious tumour immune escape. Collectively, our data suggest that Clr-b downregulation during oncogenic transformation plays a role in the detection of oncogenic transformation and cancer immunosurveillance by NK cells.