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The Inhibitory NKR-P1B:Clr-B Recognition Axis Facilitates Detection of Oncogenic Transformation and Cancer Immunosurveillance Miho Tanaka1,2, Jason H

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The Inhibitory NKR-P1B:Clr-B Recognition Axis Facilitates Detection of Oncogenic Transformation and Cancer Immunosurveillance Miho Tanaka1,2, Jason H Published OnlineFirst April 24, 2018; DOI: 10.1158/0008-5472.CAN-17-1688 Cancer Tumor Biology and Immunology Research The Inhibitory NKR-P1B:Clr-b Recognition Axis Facilitates Detection of Oncogenic Transformation and Cancer Immunosurveillance Miho Tanaka1,2, Jason H. Fine1,2, Christina L. Kirkham1,2, Oscar A. Aguilar1,2, Antoaneta Belcheva1, Alberto Martin1, Troy Ketela3,4, Jason Moffat3,4, David S.J. Allan1,2, and James R. Carlyle1,2 Abstract Natural killer (NK) cells express receptors specific for MHC class in a primary lymphoma model despite preferential rejection of – – I (MHC-I) molecules involved in "missing-self" recognition of Clr-b / hematopoietic cells previously observed following adop- cancer and virus-infected cells. Here we elucidate the role of MHC- tive transfer into na€ve wild-type mice in vivo. Collectively, these I-independent NKR-P1B:Clr-b interactions in the detection of findings suggest that the inhibitory NKR-P1B:Clr-b axis plays a oncogenic transformation by NK cells. Ras oncogene overexpres- beneficial role in innate detection of oncogenic transformation sion was found to promote a real-time loss of Clr-b on mouse via NK-cell–mediated cancer immune surveillance, in addition fibroblasts and leukemia cells, mediated in part via the Raf/MEK/ to a pathologic role in the immune escape of primary lympho- ERK and PI3K pathways. Ras-driven Clr-b downregulation ma cells in Em-cMyc mice in vivo. These results provide a model occurred at the level of the Clrb (Clec2d) promoter, nascent Clr-b for the human NKR-P1A:LLT1 system in cancer immunosur- transcripts, and cell surface Clr-b protein, in turn promoting veillance in patients with lymphoma and suggest it may rep- missing-self recognition via the NKR-P1B inhibitory receptor. resent a target for immune checkpoint therapy. Both Ras- and c-Myc–mediated Clr-b loss selectively augmented Significance: A mouse model shows that an MHC-indepen- cytotoxicity of oncogene-transformed leukemia cells by NKR- dent NK-cell recognition axis enables the detection of leukemia þ P1B NK cells in vitro and enhanced rejection by WT mice in vivo. cells, with implications for a novel immune checkpoint therapy þ – Interestingly, genetic ablation of either one (Clr-b / ) or two Clr-b target in human lymphoma. Cancer Res; 78(13); 3589–603. Ó2018 – – alleles (Clr-b / ) enhanced survival of Em-cMyc transgenic mice AACR. Introduction induced-self (3) and MHC-independent (4) modes of NK-cell recognition. Natural killer (NK) cells represent a subset of innate lymphoid One MHC-independent recognition system is the inhibitory cells (ILC) with the capacity to recognize and eliminate a variety of NKR-P1B:Clr-b interaction (5). Both the inhibitory NKR-P1B pathologic target cells, including transformed, infected, trans- receptor and its cognate Clr-b ligand are type-II transmembrane planted, antibody-coated, and stressed cells. NK cells discriminate C-type lectin-related proteins encoded within and genetically healthy 'self' cells from malignant altered-self or non-self targets linked to one another in the NK gene complex (NKC; refs. 6, 7). through interactions between a variety of germline-encoded NK- Clr-b is broadly expressed on most nucleated hematopoietic cells, cell receptors and their cognate ligands on target cells, which are similar to MHC-I molecules (7, 8). Moreover, the loss of Clr-b modulated during cellular pathologies (1). The missing-self has been shown to be involved in missing-self recognition of hypothesis was initially formulated on the basis of the observa- tumor cells (6, 7), cells infected with cytomegaloviruses (RCMV, tion that class I MHC (MHC-I)-deficient tumor cells are more MCMV) or poxviruses (Vaccinia, ectromelia; refs. 9–13), as well as efficiently recognized and eliminated by NK cells (2). More cells undergoing genotoxic or cellular stress (14). More recently, recently, this paradigm has been expanded to include both – – – – the generation of Clr-b / and NKR-P1B / mice have revealed a 1Department of Immunology, University of Toronto, Toronto, Ontario, Canada. role for this system in hematopoietic transplants, where NKR-P1B: 2Sunnybrook Research Institute, Toronto, Ontario, Canada. 3Department of Clr-b interactions function to inhibit NK-cell–mediated rejec- Molecular Genetics, University of Toronto, Ontario, Canada. 4Donnelly Centre tion of healthy syngeneic and allogeneic cells (8, 15). On the and Banting and Best Department of Medical Research, University of Toronto, other hand, cytomegaloviruses have been shown to encode Ontario, Canada. novel decoy or Clr-like surrogate ligands used to evade innate Note: Supplementary data for this article are available at Cancer Research immune detection (9, 11–13). Moreover, enforced mainte- Online (http://cancerres.aacrjournals.org/). nance of Clr-b ligand levels during tumor development has Corresponding Author: James R. Carlyle, Department of Immunology, Univer- been postulated to play a role in immunoediting and immune sity of Toronto, and Sunnybrook Research Institute, 2075 Bayview Avenue, escape of malignant cells in the Em-cMyc spontaneous lympho- Toronto, Ontario M4N 3M5, Canada. Phone: 416-480-6100, ext. 3382; Fax: 416- ma model, whereby this selective pressure is mitigated in 480-5703; E-mail: [email protected]. – – Nkrp1b / receptor–deficient mice (15). This prompted a study doi: 10.1158/0008-5472.CAN-17-1688 of Clr-b modulation during oncogenic transformation and –/– Ó2018 American Association for Cancer Research. immune surveillance in Clr-b ligand–deficient mice. www.aacrjournals.org 3589 Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst April 24, 2018; DOI: 10.1158/0008-5472.CAN-17-1688 Tanaka et al. The Ras family of proto-oncogenes was first discovered as into na€ve WT mice in vivo (8, 15). Taken together, these findings transforming elements of the Harvey and Kirsten strains of murine demonstrate an important role for the inhibitory NKR-P1B:Clr-b sarcoma viruses in mice and rats (16). Subsequently, mutated recognition system in the detection of oncogenic transformation, alleles of RAS genes were identified as dominant oncogenes in innate immunosurveillance, and the immune escape of primary various types of human tumors, with approximately 30% of lymphoma cells in vivo. These results suggest that the correspond- human malignancies bearing activating Ras mutations (16). The ing human NKR-P1A:LLT1 interaction may be a valid target for Ras proteins are small GTPases that act as molecular switches by combinatorial immune checkpoint therapy. cycling between a GTP-bound active state and a GDP-bound inactive state. Three mammalian ras genes (H-Ras, N-Ras, and Materials and Methods K-Ras) functionally encode the founding members of a larger Animals family of at least 35 related isoforms (16). These common iso- C57BL/6 (B6) and B6.CD45.1 mice were purchased from forms are highly homologous except for the C-terminal 24–25 Jackson Laboratories. FVB/N mice were purchased from Taconic. amino acids, collectively known as the hypervariable region Em-cMyc mice originally purchased from Jackson Laboratories (HVR). It is generally accepted that functional differences among were transferred from Terrence Donnelly Centre for Cellular & these Ras isoforms are attributed to the HVR (16). They exhibit – – Biomolecular Research (Toronto, Ontario, Canada). B6.Clrb / distinct posttranslational modifications, trafficking routes, and – – (Clr-b / ; refs. 8, 26) and Em-cMyc mice (27) have previously been localization in the plasma membrane, and mutations in each – – described. Em-cMyc mice were crossed to Clr-b / mice to generate isoform are associated with specific types of tumors (16). þ þ þ – – – Em-cMyc-transgenic Clr-b / , Clr-b / , and Clr-b / cohorts for NK cells are known to detect and eliminate transformed and the primary lymphoma progression model. Experiments were tumor cells through the integration of signals delivered by various performed and mice maintained under protocols approved by stimulatory (e.g., DNAM-1, NCR, NKG2D) and inhibitory recep- Animal Care Committee at Sunnybrook Research Institute (Tor- tors (e.g., Ly49/KIR, CD94/NKG2A, NKR-P1B; refs. 17–19). Thus, onto, Ontario, Canada) in compliance with guidelines from the a "missing-self" lack of inhibitory ligands, such as MHC-I mole- Canadian Council on Animal Care. cules, or an "induced-self" upregulation of stimulatory proteins, such as NKG2D ligands (NKG2D-L; ref. 20) will alter the balance of signals in favor of NK-cell–mediated target cytotoxicity. Onco- Cells genic transformation has been demonstrated to induce innate NIH3T3 cells and C1498 cells were purchased from ATCC. immune recognition in several models, including the Em-cMyc HEK 293T and BWZ.36 cells were obtained from Drs. spontaneous lymphoma model, in which NKG2D-L were shown David Raulet and Nilabh Shastri (UC Berkeley, Berkeley, CA; fl to be upregulated upon lymphoma development, in turn increas- ref. 28), and authenticated by ow cytometric analysis and ing susceptibility to NK cytotoxicity (21, 22). NKG2D-L were also b-galactosidase reporter cell activity, respectively. BWZ.CD3z/ found to be induced via the DNA damage response pathway on NKR-P1B cells were generated previously (7). All cells primary tumors derived from oncogene-transformed cells in vitro were cultured in complete DMEM-HG, supplemented with (23). Recently, it was shown that the constitutive-active H-RasG12V 2 mmol/L Glutamax (Life Technologies), 100 U/mL penicillin, oncogene upregulates NKG2D-L, including Rae1a/b (on mouse 100 mg/mL streptomycin, 50 mg/mL gentamicin, 110 mg/mL fibroblasts), and MICA/B and ULBP1-3 (on human cell lines), via sodium pyruvate, 50 mmol/L 2-mercaptoethanol, 10 mmol/L Ex vivo the Raf–MEK–ERK and PI3K pathways (24). In NIH3T3 fibro- HEPES, and 10% FBS. cells were cultured in Mycoplasma blasts, Ras-mediated oncogenic transformation was also shown to supplemented RPMI. All cell lines were tested for promote a loss of cell surface MHC-I molecules (25), which serve (MycoAlert; Lonza) at the outset of the studies.
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