Neuroblastoma as a target for effector mechanisms of the immune system
Year: 2007
Type: dissertation
Abstract: Neuroblastoma (NB) is the most common solid extracranial tumor in\nchildren. Despite intensive multimodal treatment, the prognosis for\nhigh-risk NB patients remains poor and therefore new treatment modalities\nare needed. The main aim of my studies was to assess NB as a target for\ncytotoxic T lymphocyte (CTL)-mediated immunotherapy. CTLs induce target\ncell death through two major pathways, namely the cytotoxic granule\nexocytosis- and the death receptor-mediated pathway. While an efficient T\ncell-mediated lysis through the release of perforin/granzyme-containing\ncytotoxic granules requires the expression of the relevant HLA class I\ncomplexes as well as adhesion molecules on the target cells, killing\nthrough the death receptor pathway involves the binding of the ligands to\ndeath receptors in the tumor cell membrane, and requires an intact\nintracellular molecular machinery that conveys the signal to execute\ntumor cell death. However, a number of features including low or absent\nsurface HLA class I as well as a defective expression of caspase-8, may\nhamper the development of immunotherapeutic modalities for NB.\nNevertheless, strategies to enhance the immunogenicity of NB cells could\nrender them into good targets for CTL-mediated immunotherapy.\nAlternatively, NB cells can be targeted by means of bystander activated\nCTLs in an HLA-independent fashion. Both these approaches have been\ninvestigated in the studies presented in this thesis.\n\nWe demonstrated that retinoids, differentiating agents currently in use\nas a treatment modality for high-risk NB, act as enhancers of HLA class I\nantigen processing and presentation as well as increase the\nsusceptibility of NB to CTL-mediated effector mechanisms. We found that\nretinoids induced the expression of proteolytic and regulatory subunits\nof the immunoproteasome, increased the half-life of HLA class I\ncomplexes, and enhanced the sensitivity of NB cells to both HLA class\nI-restricted peptide-specific and HLA class I non-restricted lysis by\nCTLs. Our data suggest that the application of retinoids and CTL-based\nimmunotherapy may be an effective combination for the treatment of NB\n(Paper I). Though numerous studies have demonstrated the ability of IFNγ\nto induce components of the antigen processing machinery (APM) in NB, the\nimpact on subsequent tumor recognition by CTLs has not been investigated\nin detail. Therefore, we investigated the IFNγ-induced effects on\nselected components of the APM in NB cells as well as on CTL recognition.\nAlthough IFNγ-treatment efficiently induced surface HLA class I on NB\ncells, this effect did not translate into an efficient increase in\nHLA-restricted killing by CTLs. We suggest two possible molecular\nexplanations for this phenomenon; (i) an IFNγ-induced expression of the\ninhibitory HLA-E on NB cells, and/or (ii) a decreased susceptibility of\nIFNγ-treated tumor cells to the cytolytic granule content of CTLs (Paper\nIII).\n\nTo investigate whether CTLs may eliminate NB cells in an HLA-independent\nmanner without the involvement of perforin/granzyme-mediated\ncytotoxicity, we used NB-non-specific CTLs activated on third party\ntargets as well as soluble factors released from these CTLs. We found\nthat both caspasedependent and-independent cell death were induced in NB\ncells in a bystander manner, and, in addition, TNFα released from\nactivated CTLs was defined as an important effector molecule (Paper II).\nBesides inducing NB cell death, soluble factors released by activated\nCTLs modulated the levels of cell surface molecules implicated in\nHLA-restricted and HLA-independent NB cell recognition, induced the\nexpression of caspase-8, as well as increased the susceptibility of NB\ncells to death receptor-mediated killing. Importantly, soluble factors\nreleased by activated CTLs skewed the surface immune phenotype of both\nlong term cultured and primary NB cells (Paper IV).\n\nAltogether, the results presented in this thesis suggest that recruiting\nactivated CTLs into the proximity of the tumor may have a therapeutic\neffect in patients with NB. CTLs may simultaneously activate different\ndeath pathways and override the “silent” immune phenotype of NB cells. We\nalso suggest that CTL-mediated therapy could be combined with retinoid\ntreatment of NB.
Source: Figshare
Author: Anna De Geer
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W187592144