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1 The role of NK cell receptor-expressing cell on anti-leukemia/cancer immunological effect Junji Tanaka, M.D., Ph.D. Hematology and Oncology, Hokkaido University Graduate School of Medicine Abstract NK cells recognize MHC class I molecules and inhibit the killing of target cells that have self MHC class I molecules through their inhibitory receptors. Therefore inhibitory NK receptor negatively regulate NK cell functions, including target cell lysis, through their binding to MHC class I molecules. The development of leukemia and malignant tumors might be induced as a consequence of the failure of immune surveillance. Leukemic cells and tumor cells can escape from immune recognition by cytotoxic T cells because of the low expression level of tumor antigen and/or HLA class I molecules. In such cases, non-tumor antigen-restricted cytotoxic cells such as NK cells and NK receptor-expressing cells may be important to overcome tolerance in the tumorbearing host. Donor allogeneic NK cells can attack patient's leukemic cell resulting in the enhancement of graft-versus-leukemia GVL effect and at the same time attack host antigen-presenting cells resulting in the suppression of graft-versus-host disease GVHD in allogeneic stem cell transplantation with Killer cell immunoglobulin-like receptor KIR -ligand mismatch donor. Therefore, NK cell and KIR incompatibility may have an important role in the clinical outcome of immunological cell therapy such as allogeneic stem cell transplantation for not only hematological malignancies but also solid cancers. Key words : GVHD, GVL, KIR, NK cell, Stem cell transplantation NK / GVL/T GVHD MHC class NK HLA class GVL/T HLA class GVHD GVHD/GVL HLA class NK KIR HLA class NK GVL GVHD HLA C KIR GVHD/GVL NK GVL 11

2 NK T Cytotoxic T lymphocyte CTL NK T NK Missing self 1 NK MHC class MHC class NK MHC class NK NK receptor NKR NK 2 5 NK MHC class NK MHC class I NK NK HLA class NK NK Immunoglobulin superfamily C-type lectin superfamily Table 1 Immunoglobulin superfamily Killer Ig-like receptor KIR ITIM Immunoreceptor tyrosine-based inhibitory motif L long ITIM S short Ig 2D 3D HLA C CD158 KIR2DL KIR2DL HLA C C1 Cw C2 Cw HLA Bw4 HLA A3 11 p70 p140 KIR3DL1 KIR3DL2 KIR 19 2DL1 2DL3 3DL1 A 6 ITIM KIR Table 1 12

3 KIR HLA class 6 KIR HLA class KIR HLA class NK NK NK HLA class NK GVL/T NK HLA class KIR HLA class NK GVL KIR HLA class NK NK GVL Figure 1 NK GVHD NK GVL GVHD NK 2002 Ruggeri 7 ATG T 92 bad-risk HLA C 1 HLA C 2 HLA Bw4 NK KIR GVH NK GVHD 0 20 AML event-free survival 60 NK Figure 1 13

4 NK NK GVHD NK MHC class GVL GVHD T NK T ATG KIR Ruggeri AML KIR GVHD Figure KIR KIR NK GVHD GVL T ATG NK T ATG T KIR NK GVL GVHD JMDP KIR HLA C C1/80% C2/7% C1C2/13% C1 C2 HLA C KIR GVHD 6 22 T ATG 4 1 HLA C HLA C DRB1 HLA C KIR GVHD GVHD HLA C KIR HLA C KIR ATG T KIR Figure 2 14

5 Yabe 17 JMDP KIR GVHD ATG ATG ATG KIR2DS2 GVHD HLA C HLA KIR 18 80% ATG 218 AML ALL KIR AML Figure KIR agvhd TRM 102 KIR agvhd TRM KIR ATG 41% 24% HLA KIR HLA class NK 20 NK 21 HLA NK 2x10 7 /kg NK in vitro 22 Missing-self NK MHC class NK NK KIR MHC class NK 23 KIR ligand NK KIR AML Figure 3 15

NK Figure 4 Figure 4 24 KIR MHC class NK MHC class NK NK in vitro KIR NK KIR NK GVL NK NK NK KIR 1 Ljunggren, H. G. & Karre, K. : In search of the missing self. MHC molecules and NK cell recognition.

6 NK Figure 4 Figure 4 24 KIR MHC class NK MHC class NK NK in vitro KIR NK KIR NK GVL NK NK NK KIR 1 Ljunggren, H. G. & Karre, K. : In search of the missing self. MHC molecules and NK cell recognition. Immunol Today, 11 : 237, Moretta, A., Biassoni, R., Bottino, C. et al. : Major histocompatibility complex class I-specific receptors on human natural killer and T lymphocytes. Immunol. Rev., 155 : 105, Lanier LL : NK cell receptors. Ann. Rev. Immunol., 16 : 359, Phillips, J. H., Gumperz, J. E., Parham, P., et al. : Superantigen-dependent, cell-mediated cytotoxicity inhibited by MHC class I receptors on T lymphocytes. Science. 268 : 403, Mingari, M.C., Moretta, A. & Moretta, L. : Regulation of KIR expression in human T cells : a safe mechanism that may impair protective T-cell responses. Immunol. Today, 19 : 153, Uhrberg M. The KIR gene family : life in the fast lane of evolution. Eur J Immunol. 35 : 10-15, Ruggeri L, Capanni M, Urbani E et al. Effectiveness of donor natural liller cell alloreactivity in mismatched hematopoietic transplants. Science 2002 ; 295 : Ruggeri L, Capanni M, Mancusi A, Perruccio K, Burchielli E, Martelli MF, Velardi A. Natural killer cell alloreactivity in haploidentical hematopoietic stem cell transplantation. Int J Hematol. 81 : 13-17, Ruggeri L, Mancusi A, Capanni M et al. Donor natural killer cell allorecognition of missing self in hap- 16

7 loidentical hematopoietic transplantation for acute myeloid leukemia: challenging its predictive value. Blood. 110 : , Davies SM, Ruggieri L, DeFor T, et al. Evaluation of KIR ligand incompatibility in mismatched unrelated donor hematopoietic transplants. Killer immunoglobulin-like receptor. Blood 100 : , Giebel S, Locatelli FW, Lamparelli T, et al. Survival advantage with KIR ligand incompatibility in hematopoietic stem cell transplantation from unrelated donors. Blood 31 : , Hsu KC, Gooley T, Malkki M et al. International Histocompatibility Working Group. KIR ligands and prediction of relapse after unrelated donor hematopoietic cell transplantation for hematologic malignancy. Biol Blood Marrow Transplant. 12 : , Farag SS, Bacigalupo A, Eapen M et al ; KIR Study Group, Center for International Blood and Marrow Transplantation Research. The effect of KIR ligand incompatibility on the outcome of unrelated donor transplantation: a report from the center for international blood and marrow transplant research, the European blood and marrow transplant registry, and the Dutch registry. Biol Blood Marrow Transplant. 12 : , Miller JS, Cooley S, Parham P et al. Missing KIR ligands are associated with less relapse and increased graft-versus-host disease GVHD following unrelated donor allogeneic HCT. Blood. 109 : , GVHD Morishima Y, Yabe T, Matsuo K et al. Effects of HLA allele and killer immunoglobulin-like receptor ligand matching on clinical outcome in leukemia patients undergoing transplantation with T-cellreplete marrow from an unrelated donor. Biol Blood Marrow Transplant. 13 : , Yabe T, Matsuo K, Hirayasu K et al. Donor killer immunoglobulin-like receptor KIR genotype-patient cognate KIR ligand combination and antithymocyte globulin preadministration are critical factors in outcome of HLA-C-KIR ligand-mismatched T cellreplete unrelated bone marrow transplantation. Biol Blood Marrow Transplant. 14 : 75-87, Willemze R, Rodrigues CA, Labopin M et al. KIRligand incompatibility in the graft-versus-host direction improves outcomes after umbilical cord blood transplantation for acute leukemia. Leukemia. 23 : , Brunstein CG, Wagner JE, Weisdorf DJ et al. Negative effect of KIR alloreactivity in recipients of umbilical cord blood transplant depends on transplantation conditioning intensity.blood ; : Yu J, Venstrom JM, Liu XR et al. Breaking tolerance to self, circulating natural killer cells expressing inhibitory KIR for non-self HLA exhibit effector function following T-cell depleted allogeneic hematopoietic cell transplantation. Blood : Miller JS, Soignier Y, Panoskaltsis-Mortari A et al. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood. 2005; 105 : Fujisaki H, Kakuda H, Shimasaki N et al. Expansion of highly cytotoxic human natural killer cells for cancer cell therapy. Cancer Res ; 69 : Sola C, André P, Lemmers C et al. Genetic and antibody-mediated reprogramming of natural killer cell missing-self recognition in vivo. Proc Natl Acad Sci U S A ; 106 : Romagné F, André P, Spee P et al. Preclinical characterization of 1-7F9, a novel human anti-kir receptor therapeutic antibody that augments natural killer-mediated killing of tumor cells. Blood ; 114 :

Major Histocompatibility Complex 2018; 25 (2): 抄録集 2 HLA A 3 128

Major Histocompatibility Complex 2018; 25 (: 128 138 抄録集 2018 4 14 A 3 128 MHC 2018; 25 ( HLA 2013 10.5 10 8 12 10 8 2016 CD34 + HLA NC 10 8 CD34 + CD34 + 10 6 NC10.5 2013.Apr 2014.Mar NC11 2014.Apr 2016.Jun