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DKTK - Research Program "Molecular Diagnostics, Early Detection and Biomarker Development (MDEB)"

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DKTK - „Metastasis of MSI+ colorectal cancers – a role of inhibitory immune receptors induced by tumor cell‐derived signals“

The microsatellite instability immune subgroup (MSI+) accounts for 15% of all colorectal cancers (CRC). MSI+ CRCs have a better prognosis than their MSI- negative counterparts result-ing in a lower metastasis rate.  This effect is most likely the result of the high immunogenicity of MSI tumors. Upon metastasis however, the prognosis of MSI+ cancers worsens dramatically and it is currently controversially discussed why a proportion of MSI+ tumors metastasize and to what extend BRAF, KRAS or NRAS mutations contribute to this. Our own work, as well as recent work by others have shown that BRAF and KRAS oncogenes can contribute differentially to the expression of immunomodulatory molecules and tumor infiltrating immune cells (2). Within this project we will investigate whether changes in T helper cell infiltration and expression balance of CD226 versus TIGIT/CD96 is associated with loss of immune control and metastasis of MSI+ colorectal cancers. We will analyse published data publicly available, an in house FFPE cohort (> 100 pa-tients; Institute of Pathology) and freshly collected samples provided by the surgery department. Analysis will involve immunohistochemistry, multiparameter flow cytometry and Nanostring mRNA analysis. In addition, we will also investigate expression of co-stimulatory and co-inhibitory receptors to evaluate not only the T helper cell composition but also their functional status. These results will not only provide a better understanding of mechanisms contributing to metasta-sis in MSI+ CRC samples, but likely also identify predictive markers and novel therapeutic targets for immune therapy. Furthermore, findings can be translated to other solid tumors in which loss of immune cell control is observed.

 

Project partners:

  • Prof. Dr. Birgit Sawitzki

Institute für Medizinische Immunologie

Charité Universitätsmedizin Berlin

https://immunologie.charite.de/forschung/ag_sawitzki/

 

  • PD Dr. Karsten Kamphues

Klinik für Allgemein-, Viszeral- und Gefäßchirurgie CBF – Hochschulambulanz

Charité Universitätsmedizin Berlin

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