This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Huang, J. Articles by Storkus, W. J. Search for Related Content PubMed PubMed Citation Articles by Huang, J. Articles by Storkus, W. J.

Nitric Oxide Sensitizes Tumor Cells to Dendritic Cell–Mediated Apoptosis, Uptake, and Cross-Presentation

Departments of ¹ Immunology, ² Medicine, ³ Pathology, and ⁴ Dermatology, University of Pittsburgh School of Medicine; ⁵ University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; and ⁶ Department of Molecular Therapeutics, Osaka University Graduate School of Medicine, Osaka, Japan

Requests for reprints: Walter J. Storkus, Department of Dermatology and Immunology, University of Pittsburgh School of Medicine, 1.32e Hillman Cancer Center, University of Pittsburgh Cancer Institute Research Pavilion, 5117 Centre Avenue, Pittsburgh, PA 15213. Phone: 412-623-3240; Fax: 412-623-7704; E-mail: storkuswj{at}msx.upmc.edu.

Dendritic cells are professional antigen-presenting cells associated with efficient antigen processing and presentation to T cells. However, recent evidence also suggests that dendritic cells may mediate direct tumoricidal functions. In this study, we investigated the mechanism by which murine dendritic cells mediate the apoptotic death of murine lymphoma cell lines, and whether dendritic cell effector function could be enhanced by preconditioning tumor cells with the protein phosphatase inhibitor nitric oxide (NO) by altering the balance of proapoptotic/antiapoptotic proteins in the treated cells. We observed that NO donor compound sensitized lymphomas to dendritic cell–mediated cytotoxicity in vitro. Both immature and spontaneously matured bone marrow–derived dendritic cells (SM-DC) were capable of inducing tumor cell apoptosis, with SM-DCs serving as comparatively better killers. Fas ligand (FasL)-Fas engagement proved important in this activity because elevated expression of membrane-bound FasL was detected on SM-DCs, and dendritic cells derived from FasL-deficient mice were less capable of killing NO-sensitized tumor cells than wild-type dendritic cells. As FasL-deficient dendritic cells were still capable of mediating a residual degree of tumor killing, this suggests that FasL-independent mechanisms of apoptosis are also involved in dendritic cell–mediated tumor killing. Because NO-treated tumor cells displayed a preferential loss of survivin protein expression via a proteasome-dependent pathway, enhanced tumor sensitivity to dendritic cell–mediated killing may be associated with the accelerated turnover of this critical antiapoptotic gene product. Importantly, NO-treated tumor cells were also engulfed more readily than control tumor cells and this resulted in enhanced cross-presentation of tumor-associated antigens to specific T cells in vitro.

This article has been cited by other articles:

				L. A. Smyth, N. Harker, W. Turnbull, H. El-Doueik, L. Klavinskis, D. Kioussis, G. Lombardi, and R. Lechler The Relative Efficiency of Acquisition of MHC:Peptide Complexes and Cross-Presentation Depends on Dendritic Cell Type J. Immunol., September 1, 2008; 181(5): 3212 - 3220. [Abstract] [Full Text] [PDF]

				C. Chauvin and R. Josien Dendritic Cells as Killers: Mechanistic Aspects and Potential Roles J. Immunol., July 1, 2008; 181(1): 11 - 16. [Abstract] [Full Text] [PDF]

				H. Wei, H. Wang, B. Lu, B. Li, S. Hou, W. Qian, K. Fan, J. Dai, J. Zhao, and Y. Guo Cancer Immunotherapy Using In vitro Genetically Modified Targeted Dendritic Cells Cancer Res., May 15, 2008; 68(10): 3854 - 3862. [Abstract] [Full Text] [PDF]

				C. Papewalis, B. Jacobs, M. Wuttke, E. Ullrich, T. Baehring, R. Fenk, H. S. Willenberg, S. Schinner, M. Cohnen, J. Seissler, et al. IFN-{alpha} Skews Monocytes into CD56+-Expressing Dendritic Cells with Potent Functional Activities In Vitro and In Vivo J. Immunol., February 1, 2008; 180(3): 1462 - 1470. [Abstract] [Full Text] [PDF]

				R. M. Srivastava, Ch. Varalakshmi, and A. Khar Cross-linking a mAb to NKR-P2/NKG2D on dendritic cells induces their activation and maturation leading to enhanced anti-tumor immune response Int. Immunol., May 1, 2007; 19(5): 591 - 607. [Abstract] [Full Text] [PDF]

				A. Berhanu, J. Huang, S. M. Alber, S. C. Watkins, and W. J. Storkus Combinational FLt3 Ligand and Granulocyte Macrophage Colony-Stimulating Factor Treatment Promotes Enhanced Tumor Infiltration by Dendritic Cells and Antitumor CD8+ T-Cell Cross-priming but Is Ineffective as a Therapy. Cancer Res., May 1, 2006; 66(9): 4895 - 4903. [Abstract] [Full Text] [PDF]