In this thesis, different immunotherapy strategies we employed to combat mismatch-repair-deficient (dMMR) cancer. In men, hMLH1 and hMSH2 are the most affected genes and drivers for the development of highly immunogenic dMMR-associated tumors. Hence, we used two preclinical mouse models, either having constitutional (Mlh1) or conditional (Msh2) knock out. These mice develop tumors spontaneously to nearly 100%, they can be included in therapeutic and prophylactic preclinical trials. Immunotherapy constitutes a state-of-the approach, aiming at stimulation and activation of the immune system to combat cancer.
To prevent resistance development and improve outcome, we focused on combination strategies including whole tumor vaccines, immune checkpoint-inhibitors (α-PD-L1), classical chemotherapy or the Cyclin-dependent kinase inhibitor abemaciclib. Overall survival, tumor growth, immune status, and the tumor microenvironment were studied in detail.
By applying different combination strategies, a significant survival benefit was reached in all investigated treatments. In all therapeutic approaches, increased levels of tumor infiltrating T-lymphocytes and decreased level of MDSCs were seen.
In conclusion, we found promising therapies to combat MMR-D related tumor entities. The deeper understanding of these results to finally enter clinical trials is the consequent next step.