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Tumor-Primed Human Natural Killer Cells Lyse NK-Resistant Tumor Targets: Evidence of a Two-Stage Process in Resting NK Cell Activation¹

Janet North^2,*, Ismail Bakhsh^2,*, Chloe Marden^*, Hanna Pittman^*, Elena Addison^*, Cristina Navarrete, Robert Anderson^* and Mark W. Lowdell^*,3

^* Department of Haematology, Royal Free and University College Medical School, London, United Kingdom; and Histocompatibility and Immunogenetics, National Blood Service, London, United Kingdom

NK cells are defined as those cells that lyse tumor cells without priming. In this study, we show that the preincubation of resting human NK cells with the leukemia cell CTV-1 primes NK cells to lyse NK-resistant cell lines, primary leukemias, and solid tumors even when HLA-matched, allogeneic or autologous. The primed NK cells remained nonresponsive to HLA-C matched and mismatched normal mononuclear cells from multiple donors. CD69, a known NK trigger receptor, was shown to be the predominant trigger on the tumor-primed NK cells because lysis was blocked with the rCD69 protein. The lack of lytic activity against normal hemopoietic cells implied that the ligand for CD69 is tumor restricted, and this was confirmed by experiments using fluorochrome labeled rCD69. It has been recently shown that resting NK cells require prior stimulation with IL-2 before triggering by all known NK-triggering ligands. In this study, we show that a tumor cell can provide the NK priming signal independently of IL-2. These data provide evidence for two NK evasion strategies for tumor cells, namely the prevention of priming (type1 evasion) and failure to trigger (type 2 evasion). Most NK-resistant cell lines are type 1 and fail to prime resting NK cells but are lysed by IL-2-primed NK cells. In contrast, CTV-1 cells prime resting NK cells but fail to trigger (type 2), and coincubation with CTV-1 primes for triggering by type 1 NK-resistant tumor cells. These tumor-activated NK cells lyse a broad spectrum of tumor cells with a degree of specificity never previously reported.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Leukemia Research Fund, the Association for International Cancer Research, Children with Leukaemia, and European Union Grant QLK3-2002-01936. I.B. was supported by the Government of the Kingdom of Saudi Arabia.

² J.N. and I.B. made equal contributions to this study.

³ Address correspondence and reprint requests to Dr. Mark W. Lowdell, Department of Haematology, Royal Free and University College Medical School, London, NW3 2PF, United Kingdom. E-mail address: m.lowdell{at}medsch.ucl.ac.uk

⁴ Abbreviations used in this paper: KIR, killer-like receptor; AML, acute myeloid leukemia; CML, chronic myeloid leukemia; LAK, lymphokine-activated killer cell; NCR, natural cytotoxicity receptor; T-ANK, tumor-activated NK.

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