TY  - JOUR
A1  - Diessner, Joachim
A1  - Bruttel, Valentin
A1  - Becker, Kathrin
A1  - Pawlik, Miriam
A1  - Stein, Roland
A1  - Häusler, Sebastian
A1  - Dietl, Johannes
A1  - Wischhusen, Jörg
A1  - Hönig, Arnd
T1  - Targeting breast cancer stem cells with HER2-specific antibodies and natural killer cells
JF  - American Journal of Cancer Research
N2  - Breast cancer is the most common cancer among women worldwide. Every year, nearly 1.4 million new cases of breast cancer are diagnosed, and about 450.000 women die of the disease. Approximately 15-25% of breast cancer cases exhibit increased quantities of the trans-membrane receptor tyrosine kinase human epidermal growth factor receptor 2 (HER2) on the tumor cell surface. Previous studies showed that blockade of this HER2 proto-oncogene with the antibody trastuzumab substantially improved the overall survival of patients with this aggressive type of breast cancer. Recruitment of natural killer (NK) cells and subsequent induction of antibody-dependent cell-mediated cytotoxicity (ADCC) contributed to this beneficial effect. We hypothesized that antibody binding to HER2-positive breast cancer cells and thus ADCC might be further improved by synergistically applying two different HER2-specific antibodies, trastuzumab and pertuzumab. We found that tumor cell killing via ADCC was increased when the combination of trastuzumab, pertuzumab, and NK cells was applied to HER2-positive breast cancer cells, as compared to the extent of ADCC induced by a single antibody. Furthermore, a subset of \(CD44^{high}CD24^{low}HER2^{low}\) cells, which possessed characteristics of cancer stem cells, could be targeted more efficiently by the combination of two HER2-specific antibodies compared to the efficiency of one antibody. These in vitro results demonstrated the immunotherapeutic benefit achieved by the combined application of trastuzumab and pertuzumab. These findings are consistent with the positive results of the clinical studies, CLEOPATRA and NEOSPHERE, conducted with patients that had HER2-positive breast cancer. Compared to a single antibody treatment, the combined application of trastuzumab and pertuzumab showed a stronger ADCC effect and improved the targeting of breast cancer stem cells.
KW  - trastuzumab
KW  - breast cancer
KW  - tumor stem cells
KW  - ADCC
KW  - pertuzumab
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128633
VL  - 3
IS  - 2
ER  - 
TY  - JOUR
A1  - Karikari, Akua A.
A1  - McFleder, Rhonda L.
A1  - Ribechini, Eliana
A1  - Blum, Robert
A1  - Bruttel, Valentin
A1  - Knorr, Susanne
A1  - Gehmeyr, Mona
A1  - Volkmann, Jens
A1  - Brotchie, Jonathan M.
A1  - Ahsan, Fadhil
A1  - Haack, Beatrice
A1  - Monoranu, Camelia-Maria
A1  - Keber, Ursula
A1  - Yeghiazaryan, Rima
A1  - Pagenstecher, Axel
A1  - Heckel, Tobias
A1  - Bischler, Thorsten
A1  - Wischhusen, Jörg
A1  - Koprich, James B.
A1  - Lutz, Manfred B.
A1  - Ip, Chi Wang
T1  - Neurodegeneration by α-synuclein-specific T cells in AAV-A53T-α-synuclein Parkinson’s disease mice
JF  - Brain, Behavior, and Immunity
N2  - Background
Antigen-specific neuroinflammation and neurodegeneration are characteristic for neuroimmunological diseases. In Parkinson’s disease (PD) pathogenesis, α-synuclein is a known culprit. Evidence for α-synuclein-specific T cell responses was recently obtained in PD. Still, a causative link between these α-synuclein responses and dopaminergic neurodegeneration had been lacking. We thus addressed the functional relevance of α-synuclein-specific immune responses in PD in a mouse model.
Methods
We utilized a mouse model of PD in which an Adeno-associated Vector 1/2 serotype (AAV1/2) expressing human mutated A53T-α-Synuclein was stereotactically injected into the substantia nigra (SN) of either wildtype C57BL/6 or Recombination-activating gene 1 (RAG1)\(^{-/-}\) mice. Brain, spleen, and lymph node tissues from different time points following injection were then analyzed via FACS, cytokine bead assay, immunohistochemistry and RNA-sequencing to determine the role of T cells and inflammation in this model. Bone marrow transfer from either CD4\(^{+}\)/CD8\(^{-}\), CD4\(^{-}\)/CD8\(^{+}\), or CD4\(^{+}\)/CD8\(^{+}\) (JHD\(^{-/-}\)) mice into the RAG-1\(^{-/-}\) mice was also employed. In addition to the in vivo studies, a newly developed A53T-α-synuclein-expressing neuronal cell culture/immune cell assay was utilized.
Results
AAV-based overexpression of pathogenic human A53T-α-synuclein in dopaminergic neurons of the SN stimulated T cell infiltration. RNA-sequencing of immune cells from PD mouse brains confirmed a pro-inflammatory gene profile. T cell responses were directed against A53T-α-synuclein-peptides in the vicinity of position 53 (68–78) and surrounding the pathogenically relevant S129 (120–134). T cells were required for α-synuclein-induced neurodegeneration in vivo and in vitro, while B cell deficiency did not protect from dopaminergic neurodegeneration.
Conclusions
Using T cell and/or B cell deficient mice and a newly developed A53T-α-synuclein-expressing neuronal cell culture/immune cell assay, we confirmed in vivo and in vitro that pathogenic α-synuclein peptide-specific T cell responses can cause dopaminergic neurodegeneration and thereby contribute to PD-like pathology.
KW  - Parkinson’s disease
KW  - α-synuclein-specific T cells
KW  - neurodegeneration
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300600
VL  - 101
SP  - 194
EP  - 210
ER  -