| 1. |
- Carlson, Lena-Maria, et al.
(författare)
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Differentiation induced by physiological and pharmacological stimuli leads to increased antigenicity of human neuroblastoma cells
- 2008
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Ingår i: Cell Research. - : Springer Science and Business Media LLC. - 1748-7838 .- 1001-0602. ; 18:3, s. 398-411
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Tidskriftsartikel (refereegranskat)abstract
- Sympathetic neuronal differentiation is associated with favorable prognosis of neuroblastoma (NB), the most common extra-cranial solid tumor of early childhood. Differentiation agents have proved useful in clinical protocols of NB treatment, but using them as a sole treatment is not sufficient to induce tumor elimination in patients. Therefore, complementary approaches, such as immunotherapy, are warranted. Here we demonstrate that differentiation of NB cell lines and ex vivo isolated tumor cells in response to physiological or pharmacological stimuli is associated with acquisition of increased antigenicity. This manifests as increased expression of surface major histocompatibility class I complexes and ICAM-1 molecules and translates into increased sensitivity of NB cells to lysis by cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. The latter is paralleled by enhanced ability of differentiated cells to form immune conjugates and bind increased amounts of granzyme B to the cell surface. We demonstrate, for the first time, that, regardless of the stimulus applied, the differentiation state in NBs is associated with increased tumor antigenicity that enables more efficient elimination of tumor cells by cytotoxic lymphocytes and paves the way for combined application of differentiation-inducing agents and immunotherapy as an auxiliary approach in NB patients.
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| 2. |
- Carlson, Lena-Maria, et al.
(författare)
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The microenvironment of human neuroblastoma supports the activation of tumor-associated T lymphocytes.
- 2013
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Ingår i: Oncoimmunology. - : Informa UK Limited. - 2162-4011 .- 2162-402X. ; 2:3
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Tidskriftsartikel (refereegranskat)abstract
- Tumor infiltration by lymphocytes has been linked to improved clinical outcome in children with neuroblastoma (NB) but T-cell activation has never been demonstrated to occur within the NB microenvironment. Here we show that tumor-associated lymphocytes (TALs) obtained from lesions representing all genetic subsets of NB and autologous peripheral blood lymphocytes (PBLs) analyzed on the day of tumor excision differed in composition, phenotype and functional characteristics. The NB microenvironment appeared to promote the accumulation of CD3(+)CD8(+) T cells and contained a larger proportion of T cells expressing the interleukin-2 receptor α chain (CD25) and manifesting an effector memory (CCR7(-)CD45RA(-)) phenotype. Accordingly, the stimulation of PBLs with autologous tumor cells in short-term cultures increased the proportion of effector memory T cells, upregulated CD25, stimulated the expression of the TH1 cytokines interferon γ and tumor necrosis factor α, and reduced the expression of transforming growth factor β. In situ proliferation as well as a characteristic pattern of T-cell receptor aggregation at the contact sites with malignant cells was revealed by the immunohistochemical staining of TALs in primary tumors, indicating that the NB milieu is compatible with the activation of the immune system. Our results are compatible with the hypothesis that CD8(+) T cells are specifically activated within the NB microenvironment, which appears to be permissive for effector memory responses.
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| 3. |
- Levitskaya, Jelena Vladmirovna
(författare)
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T-cell mediated control of Epstein-Barr virus infection : viral mechanisms of immune escape
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Mechanisms regulating the immunogenicity of Epstein-Barr Virus (EBV)-encoded CTL peptide epitopes and their contribution to the escape of virus infected cells from CTL-mediated immunosurveillance were the subject of these studies. It was demonstrated that two HLA A11-restricted CTL epitopes of EBV nuclear antigen (EBNA)-4 (designated IVT and AVF) possessed different immunogenicity that appeared to be due to a rapid surface turnover of All molecules containing the AVF peptide. This difference in persistence of IVT and AVF-containing complexes is likely to determine the representation of individual class I-restricted CTL epitopes within the cell surface pool of molecules and may be an important factor contributing to their immunogenicity. EBV isolates from human populations with a high frequency of HLA A11 evade recognition by CTLs specific for the IVT epitope. The epitope variants containing the substitutions in the anchor residues were able to bind to HLA A11 but formed complexes of significantly lower stability in comparison to the immunogenic epitope. In spite of the efficient production by endogenous processing and efficient association with All-molecules these complexes failed to accumulate at the cell surface, which suggests that complexes containing the non-immunogenic epitope variants are formed but are then destroyed intracellulary. Thus, a specialised sorting mechanism seems to contribute to shaping the repertoire of peptides presented to T-lymphocytes. EBV infected B-lymphocytes persist for life in healthy virus carriers. These infected cells express the EBV encoded nuclear antigen (EBNA)l but down-regulate other highly immunogenic viral products. We have shown that the glycine-alanine domain of EBNA1 generate a cis-acting inhibitory signal which interferes with antigen processing and MHC class I restricted presentation. In vitro processing assays suggest that the repeat may affect MHC class I-restricted responses by inhibiting antigen processing via the ubiquitin/ proteasome pathway. Presense of the Gly-Ala repeat was also shown to prolong half-life of EBNAl in vivo.
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