@article{AlbSieAdametal.2012,
  author    = {Alb, Miriam and Sie, Christopher and Adam, Christian and Chen, Suzie and Becker, J{\"u}rgen C. and Schrama, David},
  title     = {Cellular and cytokine-dependent immunosuppressive mechanisms of grm1-transgenic murine melanoma},
  series = {Cancer Immunology, Immunotherapy},
  volume    = {61},
  journal   = {Cancer Immunology, Immunotherapy},
  number    = {12},
  doi       = {10.1007/s00262-012-1290-9},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125096},
  pages     = {2239-2249},
  year      = {2012},
  abstract  = {Grm1-transgenic mice spontaneously develop cutaneous melanoma. This model allowed us to scrutinize the generic immune responses over the course of melanoma development. To this end, lymphocytes obtained from spleens, unrelated lymph nodes and tumor-draining lymph nodes of mice with no evidence of disease, and low or high tumor burden were analyzed ex vivo and in vitro. Thereby, we could demonstrate an increase in the number of activated CD4\(^+\) and CD8+ lymphocytes in the respective organs with increasing tumor burden. However, mainly CD4\(^+\) T cells, which could constitute both T helper as well as immunosuppressive regulatory T cells, but not CD8\(^+\) T cells, expressed activation markers upon in vitro stimulation when obtained from tumor-bearing mice. Interestingly, these cells from tumor-burdened animals were also functionally hampered in their proliferative response even when subjected to strong in vitro stimulation. Further analyses revealed that the increased frequency of regulatory T cells in tumor-bearing mice is an early event present in all lymphoid organs. Additionally, expression of the immunosuppressive cytokines TGF-β1 and IL-10 became more evident with increased tumor burden. Notably, TGF-β1 is strongly expressed in both the tumor and the tumor-draining lymph node, whereas IL-10 expression is more pronounced in the lymph node, suggesting a more complex regulation of IL-10. Thus, similar to the situation in melanoma patients, both cytokines as well as cellular immune escape mechanisms seem to contribute to the observed immunosuppressed state of tumor-bearing grm1-transgenic mice, suggesting that this model is suitable for preclinical testing of immunomodulatory therapeutics.},
  language  = {en}
}
@article{SchramaUgurelSuckeretal.2014,
  author    = {Schrama, David and Ugurel, Selma and Sucker, Antje and Ritter, Cathrin and Zapatka, Marc and Schadendorf, Dirk and Becker, J{\"u}rgen Christian},
  title     = {STAT3 Single Nucleotide Polymorphism rs4796793 SNP Does Not Correlate with Response to Adjuvant IFNα Therapy in Stage III Melanoma Patients},
  series = {Frontiers in Medicine},
  volume    = {1},
  journal   = {Frontiers in Medicine},
  number    = {47},
  issn      = {2296-858X},
  doi       = {10.3389/fmed.2014.00047},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-120602},
  year      = {2014},
  abstract  = {Interferon alpha (IFNα) is approved for adjuvant treatment of stage III melanoma in Europe and the US. Its clinical efficacy, however, is restricted to a subpopulation of patients while side effects occur in most of treated patients. Thus, the identification of predictive biomarkers would be highly beneficial to improve the benefit to risk ratio. In this regard, STAT3 is important for signaling of the IFNα receptor. Moreover, the STAT3 single-nucleotide polymorphism (SNP) rs4796793 has recently been reported to be associated with IFNα sensitivity in metastatic renal cell carcinoma. To translate this notion to melanoma, we scrutinized the impact of rs4796793 functionally and clinically in this cancer. Interestingly, melanoma cells carrying the minor allele of rs4796793 were the most sensitive to IFNα in vitro. However, we did not detect a correlation between SNP genotype and STAT3 mRNA expression for either melanoma cells or for peripheral blood lymphocytes. Next, we analyzed the impact of rs4796793 on the clinical outcome of 259 stage III melanoma patients of which one-third had received adjuvant IFNα treatment. These analyses did not reveal a significant association between the STAT3 rs4796793 SNP and patients' progression free or overall survival when IFNα treated and untreated patients were compared. In conclusion, STAT3 rs4796793 SNP is no predictive marker for the efficacy of adjuvant IFNα treatment in melanoma patients.},
  language  = {en}
}
@article{HafnerHoubenBaeurleetal.2012,
  author    = {Hafner, Christian and Houben, Roland and Baeurle, Anne and Ritter, Cathrin and Schrama, David and Landthaler, Michael and Becker, J{\"u}rgen C.},
  title     = {Activation of the PI3K/AKT Pathway in Merkel Cell Carcinoma},
  series = {PLoS One},
  volume    = {7},
  journal   = {PLoS One},
  number    = {2},
  doi       = {10.1371/journal.pone.0031255},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131398},
  pages     = {e31255},
  year      = {2012},
  abstract  = {Merkel cell carcinoma (MCC) is a highly aggressive skin cancer with an increasing incidence. The understanding of the molecular carcinogenesis of MCC is limited. Here, we scrutinized the PI3K/AKT pathway, one of the major pathways activated in human cancer, in MCC. Immunohistochemical analysis of 41 tumor tissues and 9 MCC cell lines revealed high levels of AKT phosphorylation at threonine 308 in 88\% of samples. Notably, the AKT phosphorylation was not correlated with the presence or absence of the Merkel cell polyoma virus (MCV). Accordingly, knock-down of the large and small T antigen by shRNA in MCV positive MCC cells did not affect phosphorylation of AKT. We also analyzed 46 MCC samples for activating PIK3CA and AKT1 mutations. Oncogenic PIK3CA mutations were found in 2/46 (4\%) MCCs whereas mutations in exon 4 of AKT1 were absent. MCC cell lines demonstrated a high sensitivity towards the PI3K inhibitor LY-294002. This finding together with our observation that the PI3K/AKT pathway is activated in the majority of human MCCs identifies PI3K/AKT as a potential new therapeutic target for MCC patients.},
  language  = {en}
}