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KIR receptor-ligand incompatibility predicts killing of osteosarcoma cell lines by allogeneic NK cells.

ABSTRACT: The effectiveness of killer immunoglobulin-like receptor (KIR) incompatible, alloreactive natural killer (NK) cells has been primarily documented in hematological malignancies following stem-cell transplant. This effect has not been thoroughly evaluated for pediatric solid tumors. In this study, we evaluated KIR receptor-ligand incompatibility of NK cells against osteosarcoma cell lines.Following the KIR receptor-ligand mismatch model, MHC I cell surface expression and KIR ligand mRNA content of 3 osteosarcoma cell lines was determined by flow cytometry and quantitative reverse transcription-polymerase chain reaction (qRT-PCR), respectively. NK cells were isolated from healthy volunteer donor peripheral blood mononuclear cells (PBMCs) and KIR surface expression determined by flow cytometry. An Annexin-V based flow cytometric killing assay was used to determine % of dying osteosarcoma target cells by donor NK effector cells.One of seven healthy volunteer donors tested lacked phenotypic expression of one KIR. However, variable expression of KIR ligands was observed in 3 osteosarcoma cell lines. The highest rates of dying cells were seen in osteosarcoma cells with the lowest KIR ligand expression. Following down-regulation of KIR ligand expression, an increased susceptibility to NK cell-mediated killing was observed in a previously NK-resistant osteosarcoma cell line.Variable MHC I and KIR ligand expression was observed in osteosarcoma cell lines and this resulted in variable susceptibility to NK cell-mediated killing predicted by the degree of KIR receptor-ligand incompatibility. Collectively, these data provide rationale for the study of KIR incompatible stem-cell transplant for osteosarcoma, although further studies with fresh osteosarcoma samples are necessary.

SUBMITTER: Delgado D

PROVIDER: S-EPMC3081247 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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KIR receptor-ligand incompatibility predicts killing of osteosarcoma cell lines by allogeneic NK cells.

Delgado David D Webster Daniel E DE DeSantes Kenneth B KB Durkin Emily T ET Shaaban Aimen F AF

Pediatric blood & cancer 20101201 7

<h4>Background</h4>The effectiveness of killer immunoglobulin-like receptor (KIR) incompatible, alloreactive natural killer (NK) cells has been primarily documented in hematological malignancies following stem-cell transplant. This effect has not been thoroughly evaluated for pediatric solid tumors. In this study, we evaluated KIR receptor-ligand incompatibility of NK cells against osteosarcoma cell lines.<h4>Procedure</h4>Following the KIR receptor-ligand mismatch model, MHC I cell surface expr ...[more]

PMID: 20981688

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Project description:NK cells are key players in anti tumor immune response, which can be employed in cell-based therapeutic modalities. One of the suggested ways to amplify their anti tumor effect, especially in the field of stem cell transplantation, is by selecting donor/recipient mismatches in specific HLA, to reduce the inhibitory effect of killer Ig-like receptors (KIRs). Here we suggest an alternative approach for augmentation of anti tumor effect of allogeneic NK cells, which is founded on profile matching of donor NK lysis receptors (NKLR) phenotype with tumor lysis-ligands.We show that an NKLR-mediated killing directly correlates with the NKLR expression intensity on NK cells. Considerable donor variability in the expression of CD16, NKp46, NKG2D and NKp30 on circulating NK cells, combined with the stability of phenotype in several independently performed tests over two months, indicates that NKLR-guided selection of donors is feasible. As a proof of concept, we show that melanoma cells are dominantly recognized by three NKLRs: NKG2D, NKp30 and NKp44. Notably, the expression of NKp30 on circulating NK cells among metastatic melanoma patients was significantly decreased, which diminishes their ability to kill melanoma cells. Ex vivo expansion of NK cells results not only in increased amount of cells but also in a consistently superior and predictable expression of NKG2D, NKp30 and NKp44. Moreover, expanded NK cultures with high expression of NKG2D or NKp30 were mostly derived from the corresponding NKG2D(high) or NK30(high) donors. These NK cultures subsequently displayed an improved cytotoxic activity against melanoma in a HLA/KIR-ligand mismatched setup, which was NKLR-dependent, as demonstrated with blocking anti-NKG2D antibodies.NKLR/NKLR-ligand matching reproducibly elicits enhanced NK anti-tumor response. Common NKLR recognition patterns of tumors, as demonstrated here in melanoma, would allow implementation of this approach in solid malignancies and potentially in hematological malignancies, either independently or in adjunction to other modalities.

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KIR receptor-ligand incompatibility predicts killing of osteosarcoma cell lines by allogeneic NK cells.

Publications

KIR receptor-ligand incompatibility predicts killing of osteosarcoma cell lines by allogeneic NK cells.

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