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

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The Inhibitory NKR-P1B:Clr-B Recognition Axis Facilitates Detection of Oncogenic Transformation and Cancer Immunosurveillance Author Manuscript Published OnlineFirst on April 24, 2018; DOI: 10.1158/0008-5472.CAN-17-1688 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 2 3 The inhibitory NKR-P1B:Clr-b recognition axis facilitates detection of oncogenic 4 transformation and cancer immunosurveillance 5 6 Miho Tanaka1,2, Jason H. Fine1,2, Christina L. Kirkham1,2, Oscar A. Aguilar1,2, Antoaneta 7 Belcheva1, Alberto Martin1, Troy Ketela3,4, Jason Moffat3,4, David S.J. Allan1,2, and 8 James R. Carlyle*1,2 9 10 1Department of Immunology, University of Toronto, Toronto, ON, Canada. 11 2Sunnybrook Research Institute, Toronto, ON, Canada. 12 3Department of Molecular Genetics, University of Toronto, ON, Canada. 13 4Donnelly Centre and Banting and Best Department of Medical Research, University of 14 Toronto, ON, Canada. 15 16 Corresponding Author: James R. Carlyle, Department of Immunology, University of 17 Toronto, and Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ON, 18 Canada M4N 3M5. Phone: 416-480-6100, ext. 3382; Fax: 416-480-5703; E-mail: 19 [email protected]. 20 21 Conflicts of Interest 22 None to disclose. 23 24 25 26 27 28 Keywords: Natural killer cell, missing-self recognition, oncogenic transformation, cancer 29 immune surveillance, immune checkpoint, lymphoma, Klrb1, Clec2d, CD161, LLT1. 30 Running title: Oncogene transformation promotes missing-self NK recognition 31 1 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 24, 2018; DOI: 10.1158/0008-5472.CAN-17-1688 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 32 ABSTRACT 33 Natural killer (NK) cells express receptors specific for MHC class I (MHC-I) 34 molecules involved in “missing-self” recognition of cancer and virus-infected cells. Here 35 we elucidate the role of MHC-I-independent NKR-P1B:Clr-b interactions in the detection 36 of oncogenic transformation by NK cells. Ras oncogene overexpression was found to 37 promote a real-time loss of Clr-b on mouse fibroblasts and leukemia cells, mediated in 38 part via the Raf/MEK/ERK and PI3K pathways. Ras-driven Clr-b downregulation 39 occurred at the level of the Clrb (Clec2d) promoter, nascent Clr-b transcripts, and cell 40 surface Clr-b protein, in turn promoting missing-self recognition via the NKR-P1B 41 inhibitory receptor. Both Ras- and c-Myc-mediated Clr-b loss selectively augmented 42 cytotoxicity of oncogene-transformed leukemia cells by NKR-P1B+ NK cells in vitro and 43 enhanced rejection by WT mice in vivo. Interestingly, genetic ablation of either one (Clr- 44 b+/–) or two Clr-b alleles (Clr-b–/–) enhanced survival of E-cMyc transgenic mice in a 45 primary lymphoma model despite preferential rejection of Clr-b–/– hematopoietic cells 46 previously observed following adoptive transfer into naïve wild-type mice in vivo. 47 Collectively, these findings suggest that the inhibitory NKR-P1B:Clr-b axis plays a 48 beneficial role in innate detection of oncogenic transformation via NK cell-mediated 49 cancer immune surveillance, in addition to a pathological role in the immune escape of 50 primary lymphoma cells in E-cMyc mice in vivo. These results provide a model for the 51 human NKR-P1A:LLT1 system in cancer immunosurveillance in lymphoma patients and 52 suggest it may represent a target for immune checkpoint therapy. 53 2 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 24, 2018; DOI: 10.1158/0008-5472.CAN-17-1688 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 54 INTRODUCTION 55 Natural killer (NK) cells represent a subset of innate lymphoid cells (ILC) with 56 the capacity to recognize and eliminate a variety of pathological target cells, including 57 transformed, infected, transplanted, antibody-coated, and stressed cells. NK cells 58 discriminate healthy ‘self’ cells from malignant altered-self or non-self targets through 59 interactions between a variety of germline-encoded NK cell receptors and their cognate 60 ligands on target cells, which are modulated during cellular pathologies (1). The missing- 61 self hypothesis was initially formulated based on the observation that class I MHC 62 (MHC-I)-deficient tumor cells are more efficiently recognized and eliminated by NK 63 cells (2). More recently, this paradigm has been expanded to include both induced-self (3) 64 and MHC-independent (4) modes of NK cell recognition. 65 One MHC-independent recognition system is the inhibitory NKR-P1B:Clr-b 66 interaction (5). Both the inhibitory NKR-P1B receptor and its cognate Clr-b ligand are 67 type-II transmembrane C-type lectin-related proteins encoded within and genetically 68 linked to one another in the NK gene complex (NKC) (6,7). Clr-b is broadly expressed on 69 most nucleated hematopoietic cells, similar to MHC-I molecules (7,8). Moreover, the loss 70 of Clr-b has been shown to be involved in missing-self recognition of tumor cells (6,7), 71 cells infected with cytomegaloviruses (RCMV, MCMV) or poxviruses (Vaccinia, 72 ectromelia) (9-13), as well as cells undergoing genotoxic or cellular stress (14). More 73 recently, the generation of Clr-b–/– and NKR-P1B–/– mice have revealed a role for this 74 system in hematopoietic transplants, where NKR-P1B:Clr-b interactions function to 75 inhibit NK cell-mediated rejection of healthy syngeneic and allogeneic cells (8,15). On 76 the other hand, cytomegaloviruses have been shown to encode novel decoy or Clr-like 77 surrogate ligands used to evade innate immune detection (9,11-13). Moreover, enforced 78 maintenance of Clr-b ligand levels during tumor development has been postulated to play 79 a role in immunoediting and immune escape of malignant cells in the E-cMyc 80 spontaneous lymphoma model, whereby this selective pressure is mitigated in Nkrp1b–/– 81 receptor-deficient mice (15). This prompted a study of Clr-b modulation during 82 oncogenic transformation and immune surveillance in Clr-b–/– ligand-deficient mice. 83 The Ras family of proto-oncogenes was first discovered as transforming elements 84 of the Harvey and Kirsten strains of murine sarcoma viruses in mice and rats (16). 3 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 24, 2018; DOI: 10.1158/0008-5472.CAN-17-1688 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 85 Subsequently, mutated alleles of RAS genes were identified as dominant oncogenes in 86 various types of human tumors, with ~30% of human malignancies bearing activating 87 Ras mutations (16). The Ras proteins are small GTPases that act as molecular switches by 88 cycling between a GTP-bound active state and a GDP-bound inactive state. Three 89 mammalian ras genes (H-Ras, N-Ras, and K-Ras) functionally encode the founding 90 members of a larger family of at least 35 related isoforms (16). These common isoforms 91 are highly homologous except for the C-terminal 24-25 amino acids, collectively known 92 as the hypervariable region (HVR). It is generally accepted that functional differences 93 among these Ras isoforms are attributed to the HVR (16). They exhibit distinct post- 94 translational modifications, trafficking routes, and localization in the plasma membrane, 95 and mutations in each isoform are associated with specific types of tumors (16). 96 NK cells are known to detect and eliminate transformed and tumor cells through 97 the integration of signals delivered by various stimulatory (e.g., DNAM-1, NCR, 98 NKG2D) and inhibitory receptors (e.g. Ly49/KIR, CD94/NKG2A, NKR-P1B) (17-19). 99 Thus, a “missing-self” lack of inhibitory ligands, such as MHC-I molecules, or an 100 “induced-self” upregulation of stimulatory proteins, such as NKG2D ligands (NKG2D-L) 101 (20) will alter the balance of signals in favor of NK cell-mediated target cytotoxicity. 102 Oncogenic transformation has been demonstrated to induce innate immune recognition in 103 several models, including the E-cMyc spontaneous lymphoma model, in which 104 NKG2D-L were shown to be upregulated upon lymphoma development, in turn 105 increasing susceptibility to NK cytotoxicity (21,22). NKG2D-L were also found to be 106 induced via the DNA damage response pathway on primary tumors derived from 107 oncogene-transformed cells in vitro (23). Recently, it was shown that the constitutive- 108 active H-RasG12V oncogene upregulates NKG2D-L, including Rae1/ (on mouse 109 fibroblasts), and MICA/B and ULBP1-3 (on human cell lines), via the Raf-MEK-ERK 110 and PI3K pathways (24). In NIH3T3 fibroblasts, Ras-mediated oncogenic transformation 111 was also shown to promote a loss of cell surface MHC-I molecules (25), which serve as 112 ligands for inhibitory Ly49 receptors. 113 How transformation or primary tumorigenesis influence Clr-b expression are 114 currently unknown. Here, we show that overexpression of wild-type (WT) or 115 constitutive-active (CA), but not dominant-negative (DN), Ras isoforms downregulate 4 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 24, 2018; DOI: 10.1158/0008-5472.CAN-17-1688 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 116 surface Clr-b levels on NIH3T3 fibroblasts and C1498 leukemia cells. The loss of surface 117 Clr-b coincides with a decrease in nascent Clr-b (Clec2d) transcripts and promoter 118 activity. Similar to NKG2D-L induction, RasG12V-mediated Clr-b downregulation occurs 119 via the Raf-MEK-ERK and PI3K pathways.
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