Immune response in anaplastic thyroid carcinoma after MAPK pathway inhibition

• Applicant: Dr. Vera Tiedje
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: from 2017 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 390533080

Anaplastic thyroid carcinoma (ATC) is responsible for most thyroid cancer related deaths. So far there is no established therapy regimen. Recent massive parallel sequencing studies have shown that ATC is characterized by high mutational burden due to the accumulation of somatic mutations. The mutations are mainly located in the p53 gene, TERT promoter, PI3K and BRAF encoding genes. A clinically relevant issue is to use information on mutations in targetable genes to develop novel treatment approaches. Recent case reports have shown that targeted BRAF inhibition results in tumour shrinkage in BRAF positive ATC. However duration of response is limited. Moreover, it is known in other aggressive tumours, that higher mutational burden is associated with higher likelihood of treatment response to immunotherapy. Moreover, there is increasing data suggesting an interplay between MAPK activation through BRAFV600E mutation and the tumour microenvironment. Therefore, the response to pharmacological MAPK inhibition might be mediated by the immune system. However, the effector cells involved and the mechanisms of interaction e.g. through influencing gene expression of the effector immune cells is yet unknown. Therefore the hypotheses are that (i) ATC tumour regression by oncogenic BRAF inhibition requires immune cell clearance and that (ii) the medium to long-term response to pharmacological BRAF inhibition is impaired by MAPK inhibition in immune cells that suppresses their ability to respond.To answer those hypotheses a suitable mouse model is needed. Transgenic dox-inducible BRAFV600E mice develop large ATC after p53 loss. This model allows studying pharmacological versus genetic BRAF inhibition by doxycycline-withdrawal. The interaction between the MAPK-pathway and the immune microenvironment will be analysed by characterizing immune infiltrates in the setting of tumour-specific MAPK inhibition versus pharmacological MAPK inhibition and furthermore it will be determined whether inhibiting MAPK-signaling in immune cells affects their ability to respond. The consequence of depleting immune effector cells like T, B and NK cells on tumour response to BRAF inhibition is studied and if the upregulation of immune checkpoint proteins correlates with response to immune therapy. The results will elucidate immune-mediated tumour evasion mechanisms in ATC and will contribute to the development of new treatment options.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor James Fagin