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

Abstract

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 proteasomedependent 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. (Cancer Res 2005; 65(18): 8461-70)

Interactions of tumor cells with dendritic cells: balancing immunity and tolerance

“…144 Taken together, these emerging data suggest that different DC subsets may have both tumor-promoting as well as tumor-suppressive properties in vivo. This can be exemplified by the demonstration that breast cancer instructs DCs to induce CD4 þ T cells secreting IL13 and promote cancer development by mediating DC polariziation.…”

The ‘kiss of death’ by dendritic cells to cancer cells

“…72,73 Immature DCs have also been shown to kill freshly isolated tumors. [74][75][76] Although in vitro-derived immature DCs kill target cells very efficiently at low effector/target ratios via an apoptotic mechanism involving DNA fragmentation, mitochondrial dysfunction, and late membrane disruption, the level of cytotoxicity found in the freshly isolated, immature DCs remains low and questionable. 75 To note, while Chen's group 70 demonstrated that the tumor killing by immature DCs is mediated through direct cell-to-cell contact, Vujanovic's group 75 showed, using the same type of immature DCs, that the killing mechanism was mediated by both cell-to-cell contact and soluble mediators.…”

“…It is believed that CD40L-induced robust TNF-a secretion exerts a differential effect on target cell death according to the balance of pro-apoptotic signals/ pro-NF-kB signals. Huang et al 74 recently reported that bone marrow-derived DCs mediate cytotoxic activity toward B-cell lymphoma. Interestingly, they showed that by disrupting the balance of pro-apoptotic versus anti-apoptotic signals, target cells can be sensitized to TNF family ligand-mediated apoptosis.…”

Killer dendritic cells: mechanisms of action and therapeutic implications for cancer

“…Indeed, the NO-dependency of KDC lysis observed by Srivastava et al 9 may reflect the reported ability of NO to sensitize tumor cell targets to apoptosis mediated by KDC via Fas, etc. 13 …”

“…Interestingly, it appears that such in vitro generated DC exhibit most potent cytotoxic potential after undergoing 'spontaneous' maturation (occurring over time in the absence of known exogenous activators). 13 TNF family members including FasL, TRAIL and TNF-a are expressed by cultured immature and spontaneously-matured BM-DC, 4,13 allowing these KDC to promote the apoptosis of human Jurkat cells and the murine A20 B cell lymphoma, with Fas-L (-/-) DC proving inferior in KDC function. 13 Furthermore, transduction of BM-DC with adenovirus constructs encoding mIL-12p70 and mIL-18 leads to enhanced TNF-a and TRAIL expression and improved KDC function against syngenic CMS4 sarcoma cells.…”