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Activation of Immature Hepatic NK Cells As Immunotherapy for Liver Metastatic Disease

Keith S. Bahjat^1,2,*, Rodney A. Prell^1,*, Heather E. Allen^*, Weiqun Liu^*, Edward E. Lemmens^*, Meredith L. Leong^*, Daniel A. Portnoy, Thomas W. Dubensky, Jr.^2,*, Dirk G. Brockstedt^* and Martin A. Giedlin^*

^* Cerus Corporation, Concord, CA 94520; and Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720

NK cells can identify and eliminate emerging tumors due to altered expression of activating and inhibitory ligands on aberrant cells, a process that is greatly enhanced following NK cell activation. As a principal site of both tumor metastases and immature NK cells, the liver represents a unique anatomic location in which activation of the innate immune system could provide substantial therapeutic benefit. We describe here the NK cell-dependent destruction of a primary hepatic tumor following infection with an attenuated intracellular bacterium derived from Listeria monocytogenes. NK cell-mediated immunity correlated with the ordered migration and maturation of NK cells within the liver. Cytolytic activity was partially dependent on NKG2D-mediated tumor cell recognition, but surprisingly was still effective in the absence of type I IFN. Significantly, NK cell-mediated destruction of a primary hepatic tumor in infected mice led to long-lived CD4- and CD8 T cell-dependent tumor-specific adaptive immunity. These findings establish that activation and differentiation of immature NK cells using complex microbial stimuli can elicit potent anti-tumor activity within the liver, promote cross-presentation of tumor-derived Ags leading to long-lived systemic anti-tumor immunity, and suggests a paradigm for clinical intervention of liver metastatic carcinoma.

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 K.S.B. and R.A.P. contributed equally to this work.

² Address correspondence and reprint requests to Dr. Keith S. Bahjat or Dr. Thomas W. Dubensky, Jr., Cerus Corporation, 2411 Stanwell Drive, Concord, CA 94520. E-mail addresses: reprints{at}keithbahjat.com and tom_dubensky{at}cerus.com

³ Abbreviations used in this paper: CRC, colorectal cancer; LLO, cytolysin listeriolysin O; DC, dendritic cell; MST, median survival time.