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NK Cells Use NKG2D to Recognize a Mouse Renal Cancer (Renca), yet Require Intercellular Adhesion Molecule-1 Expression on the Tumor Cells for Optimal Perforin-Dependent Effector Function¹

Karen Abdool^*,, Erika Cretney^¶, Alan D. Brooks, Janice M. Kelly^¶, Jeremy Swann^¶, Anil Shanker, Earl W. Bere, Jr.^*, Wayne M. Yokoyama, John R. Ortaldo^*, Mark J. Smyth^2,¶ and Thomas J. Sayers^2,3,

^* Laboratory of Experimental Immunology, National Cancer Institute-Frederick, Center for Cancer Research and Basic Research Program, SAIC-Frederick, National Cancer Institute Frederick, Center for Cancer Research-Frederick, Frederick, MD; Department of Microbiology, College of Medicine, Howard University, Washington D.C.; Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO; and ^¶ Cancer Immunology Program, Trescowthick Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia

The NKG2D receptor on NK cells can recognize a variety of ligands on the tumor cell surface. Using a mouse renal cancer (Renca), we show that NKG2D recognition by NK cells was crucial for their ability to limit tumor metastases in vivo in both liver and lungs using perforin-dependent effector mechanisms. However, for the R331 cell line established from Renca, NKG2D recognition and perforin-dependent lysis played no role in controlling liver metastases. R331 cells were also more resistant to perforin-dependent lysis by NK cells in vitro. We therefore used these phenotypic differences between Renca and R331 to further investigate the crucial receptor:ligand interactions required for triggering lytic effector functions of NK cells. Reconstitution of R331 cells with ICAM-1, but not Rae-1, restored NKG2D-mediated, perforin-dependent lysis. Interestingly, R331 cells were efficiently lysed by NK cells using death ligand-mediated apoptosis. This death ligand-mediated killing did not depend on NKG2D recognition of its ligands on tumor cells. This result suggests that the intracellular signaling in NK cells required for perforin and death ligand-mediated lysis of tumor target cell are quite distinct, and activation of both of these antitumor lytic effector functions of NK cells could improve therapeutic benefits for certain tumors.

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