Tumor necrosis factor- (TNF), originally described as a death-inducer in tumor cells, is also knownas an effector molecule of NK-cells and cytotoxic T-lymphocytes (CTL) involved in tumor rejection.However, accumulating evidence suggests that TNF can also be a tumor promoting factor. Weobserved expression of membrane-associated TNF on the surface of neuroblastoma (NB) cellsderived from humans or mice. Disruption of TNF:TNF-R(s) interactions, using blocking antibodies orsoluble TNF-R2, decreased human NB cell viability indicating that TNF constitutively generates a pro-survival signal. Similar data were obtained using NB tumors spontaneously arising in transgenic TH-MYCN mice. Neutralization of TNF was also associated with downregulation of MHC class I in NBcells and led to their decreased susceptibility to perforin and granzyme B, the major components ofcytotoxic granules of CTLs and NK cells. We also observed loss of tumor cell capacity to trigger theinhibitory CD94 heterodimer on cytotoxic lymphocytes. Thus, TNF appears to induce phenotypicchanges with potentially opposing effects on CTL and NK recognition of NB cells. However, ourresults suggest that decreased recognition of NB-cell by both CTLs and NK cells is the net effect ofautochthonous TNF activity. This research program proposes to use primary human and mouse NBcells as a model for dissecting the role of tumor-produced TNF in regulating survival, antigenpresentation and sensitivity to perforin/granzyme mediated death in tumor cells. The in vivo effects ofTNF blockade in NB cells will be investigated using spontaneous model of murine neuroblastoma andxenotransplantation of human NB cells into the immunodeficient mice. We will also characterize TNF-induced signals and pathways regulating susceptibility to cytotoxic lymphocytes either at the level oftarget sensitivity or effector activation. Detailed knowledge of such signals will improve ourunderstanding of the pathogenesis of autoimmune disorders, allograft rejection and tumor immuneescape. We believe that our research will also shed light on the molecular mechanisms of NBtumorogenesis and lead to the development of new strategies of NB therapy based on blockade ofendogenous TNF. Importantly, a spectrum of TNF blockers is already approved and successfullyapplied in clinical settings. Characterization of TNF function in neuroblastoma will promptinvestigations on the role of this cytokine in the pathogenesis of other tumors.
We observed that membrane bound Tumor necrosis factor (TNF) alfa is expressed on the surface of neuroblastoma (NB) cells and its functional blockade leads to decreased tumor viability and increased tumor susceptibility to killing by cytotoxic lymphocytes. Investigations on the role of tumor-produced TNF in regulating survival, proliferation and antigenic characteristics of NB cells will improve our understanding of the pathogenesis of autoimmune disorders, allograft rejection and tumor immune escape.
| Carlson, Lena-Maria; De Geer, Anna; Sveinbjørnsson, Baldur et al. (2013) The microenvironment of human neuroblastoma supports the activation of tumor-associated T lymphocytes. Oncoimmunology 2:e23618 |
