Targeting KRAS-driven tumours via their dependence on PTPN11/SHP2-phosphatase to enhance anti-tumour immunity

Project Summary

P17 will assess if indirect interference with oncogenic KRAS signalling output via SHP2- and MEK-inhibition can reverse the immunosuppressive properties of mutant KRAS in pancreatic and colorectal cancer. This approach relies on previous findings that adequate function of mutant KRAS depends on presence and activity of the tyrosine phosphatase SHP2, encoded by PTPN11. In a translational approach, P17 will use KRAS mutant syngeneic murine and human PTPN11 knockout tumour models to identify changes in the tumour-immune-microenvironment and to exploit resulting immunotherapeutic vulnerabilities. Further, P17 will elaborate the impact of SHP2- and MEK-inhibition on homeostasis of tumor-associated macrophages and CD4-T-cell subsets in vivo and ex vivo.