Nitric oxide sensitizes tumor cells to dendritic cell-mediated apoptosis, uptake, and cross-presentation.
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.
Huang
Jian
J
Department of Immunology, University of Pittsburgh School of Medicine, Pennsylvania 15213, USA.
Tatsumi
Tomohide
T
Pizzoferrato
Eva
E
Vujanovic
Nikola
N
Storkus
Walter J
WJ
D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D045744:Cell Line, Tumor; D003429:Cross Reactions; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D053222:Fas Ligand Protein; D051034:Inhibitor of Apoptosis Proteins; D008223:Lymphoma / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000276:immunology / Q000378:metabolism; D009569:Nitric Oxide / Q000493:pharmacokinetics / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000493:pharmacokinetics / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D012097:Repressor Proteins; D000077022:Survivin; D013601:T-Lymphocytes / Q000276:immunology; D019014:fas Receptor / Q000276:immunology
D000951:Antigens, Neoplasm; C117749:Birc5 protein, mouse; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D008562:Membrane Glycoproteins; D008869:Microtubule-Associated Proteins; D020030:Nitric Oxide Donors; D012097:Repressor Proteins; D000077022:Survivin; D019014:fas Receptor; D009569:Nitric Oxide; D046988:Proteasome Endopeptidase Complex