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

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 () 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 and enhanced rejection by WT mice 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 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 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. 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. .

Lectin-like transcript 1 as an natural killer cell-mediated immunotherapeutic target for triple negative breast cancer and prostate cancer

“…Santos-Juanes' newest study showed higher LLT1 expression was contributed to the risk of neck cutaneous squamous cell carcinoma (cSCC) nodal metastasis, which implicates LLT1 may also be a potential target to block cSCC nodal metastasis [57] . Similar results have also been seen in mice; inhibition of NKRP1B: Clr-b axis could enhance the NK cell-mediated immune surveillance to oncogenic transformation [52] . Due to the important role of LLT1 in tumor progression and metastasis, monoclonal antibody blocking of LLT1 to enhance NK cell cytotoxicity may provide a novel treatment to prevent tumor metastasis.…”

“…NKRP1A is encoded by KLRB1 and CD4 + T cells, invariant NKT cells, and γδ-T cells have also been shown to express NKRP1A [49] . In mice, CLEC2D encodes the protein Ocil/Clr-b, which interacts with NKR-P1B/D [52][53][54] .…”

Production of recombinant soluble dimeric C-type lectin-like receptors of rat natural killer cells

“…However, a similar host-pathogen evolutionary interplay is revealed by the engagement of some of the m12 alleles through the activating NKR-P1A/C receptors that avert the MCMV decoy strategy 22 . The mouse Clr-b ligand is also a very sensitive marker of cell health that is rapidly downregulated during chemotherapy-induced genotoxic and cellular stress 23 or poxvirus infection 24 or oncogenesis25 . Concomitantly, recent studies showed that NKR-P1B:Clr-b missing-self recognition plays a key and non-redundant role in bone marrow transplantation 26,27 and cancer immunosurveillance25 in a mouse models.…”

Bispecific T-Cell Redirection versus Chimeric Antigen Receptor (CAR)-T Cells as Approaches to Kill Cancer Cells

“…The biotechnology company, TCR2, is exploring CD3ε-scFv fusions (Figure 10). Utilizing their TruC platform, the tumor specific binding scFv is fused to the extracellular domain of CD3ε, allowing for complex activation upon scFv-target binding, bypassing TCRα/β-MHC interactions [333]. Similarly, Triumvira has fused two scFvs in place of the MHC I binding head domain of CD8.…”