Enhanced cytotoxicity of allogeneic NK cells with killer immunoglobulin-like receptor ligand incompatibility against melanoma and renal cell carcinoma cells

Abstract

IntroductionNatural killer (NK) cells have antigen-independent tumor cytotoxicity and have been shown in murine models to control and prevent tumor growth and dissemination. 1,2 However, the exact role that NK cells play in the control of cancer in humans remains a matter of controversy.NK cells do not rearrange genes coding for specific antigen receptors; rather, their recognition of targets is regulated through a balance of activating or inhibitory signals. 3 It is necessary to inactivate NK cells to prevent their destruction of normal host tissues. 4 Therefore, even in the presence of an activating ligand, inhibitory ligands expressed on cells may deliver overriding signals that culminate in a net suppression of NK cell function. Recently, a growing number of NK cell inhibitory and activating receptors were characterized. 5-8 NK cells can recognize major histocompatibility (MHC) class I and class I-like molecules through killer immunoglobulin-like receptors (KIRs) expressed on their surfaces. MHC class I ligation of KIRs on normal and malignant tissues suppresses NK cell function. MHC class I molecules fall into groups that serve as ligands for specific KIR, resulting in the inhibition of NK cell-mediated cytotoxicity. Polymorphisms in amino acids residing at positions 77 and 80 of HLA-C dictate specificity for its target KIR. 9-11 KIR2DL1 recognizes group 2 HLA-C molecules that have an asparagine at position 77 and a lysine at position 80, whereas KIR2DL2 and KIR2DL3 recognize group 1 HLA-C molecules that have a serine at position 77 and an asparagine at position 80.The inactivation of NK cells by self-HLA molecules might be a mechanism permitting malignant host cells to evade NK cellmediated immunity. Because tumor KIR ligands are always matched to NK cell KIR, autologous NK cells would be inhibited by MHC class I-expressing tumors, even in the presence of activating ligands. This may in part explain the failure of adoptively transfused autologous NK 12 or lymphokine-activated killer (LAK) cells to mediate antitumor effects against most metastatic solid tumors. 13 Only tumor cells that have lost MHC class I expression or have a dominant-activating ligand are predicted to be susceptible to such populations. 14 Ruggeri et al 15,16 and others 17 have shown allogeneic NK cells can mediate antileukemic effects against AML after allogeneic haploidentical and partially mismatched unrelated hematopoietic cell transplantation when KIR/KIR ligand incompatibility exists in the graft-versus-host (GVH) direction (defined as an MHC class I KIR ligand that is absent in the recipient but present in the donor). In this setting, donor NK cells expand that are not inhibited by For personal use only. on March 22, 2019. by guest www.bloodjournal.org From ligands expressed on recipient leukemia cells, substantially reducing the risk for disease relapse compared with those who receive KIR-compatible transplants. This beneficial effect does not appear to occur against acute lymphoblastic leukemia (ALL), perhaps because these popul...

Keratinocyte growth factor ameliorates acute graft-versus-host disease in a novel nonmyeloablative haploidentical transplantation model

“…It has been shown that donor T cells are indeed crucial for recovery of immune function after haploidentical transplantations. 49 Adding KGF treatment to haploidentical transplantations, possibly in combination with standard GVHD prophylaxis, 50 might therefore be a valuable clinical option, allowing more transplantations to be performed safely without serious GVHD and immunodeficiency.…”

NK Cells and Cancer

“…A recent report (72) demonstrates that KIR-incompatible allogeneic NK cells have superior antitumor effects against fresh tumor cells isolated from different solid cancers, as well as against MEL and RCC established tumor cell lines (73). Interactions between solid tumor cells and the microenvironment in vivo create a context that promotes tumor growth, selection, and protection from immune attack, suggesting that the tridimensional architecture of solid cancer lesions is likely one of the tumor mechanisms to escape immunosurveillance (70).…”

Use of natural killer cells in hematopoetic stem cell transplantation

“…Some encouraging data comes from work with solid tumors. 49 Whether NK cells will be used without additional manipulation, or whether stimulation and culture either short or medium term with cytokines such as IL-2 will prove to be more effective awaits further studies. 50 Purging and enrichment technology using magnetic beads for clinical application is technologically fascinating but expensive, in direct costs of antibodies and columns and the time of laboratory personnel.…”