Investigation of the relationship between immune checkpoints and target signal pathways in pancreas cancer

Pancreatic cancer is considered one of the most lethal cancers due to its aggressive clinical course, late-stage diagnosis, and limited response to current treatment approaches. The immunosuppressive nature of the tumor microenvironment and genetic heterogeneity severely limit the effectiveness of immunotherapeutic approaches in this cancer type. In this context, a better understanding of immune checkpoint molecules involved in immune escape mechanisms at the molecular level and the elucidation of the relationship between these targets and regulatory signaling pathways are critical for developing new treatment strategies. This doctoral dissertation focused on the gene and protein regulation of immune checkpoint molecules such as VISTA, PD-L1, CD155, HVEM, and IDO1, which suppress the immune system in pancreatic cancer. The potential signaling pathways affecting the expression levels of these molecules were experimentally investigated using various small molecule inhibitors. The use of unique chemical agents such as vorinostat, PF-562271, navoximod, importazole, and sepantronium bromide, both individually and in combination, in pancreatic cancer cell lines (Mia PaCa-2, BxPC-3, AsPC-1, PANC-1, and CAPAN-1) has led to comprehensive investigations of their antiproliferative effects, roles in cell migration and colony formation, apoptosis mechanisms, and regulatory effects on immune checkpoint expression. The study demonstrated that the expression levels of VISTA, PD-L1, and CD155 molecules were significantly suppressed by certain compound combinations, while genes involved in tumor progression, such as TRIM15, Twist1, AGR2, LEF1, and BIRC5, were also modulated. Furthermore, it was determined that the administration of the BIRC5 inhibitor sepantronium bromide, both alone and in combination with navoximod, suppressed immune checkpoints only in tumor cells without affecting healthy cell proliferation and migration. These findings hold significant potential for immunotherapeutic strategies that could contribute to the reprogramming of the treatment-resistant tumor microenvironment. This thesis evaluated pancreatic cancer biology from multiple perspectives, including immune regulation, epigenetic control, the cell cycle, and the tumor microenvironment. The data revealed how immune checkpoint molecules interact with diverse signaling pathways, demonstrating that simultaneous targeting of these molecules could offer a powerful strategy for overcoming immune escape mechanisms and enhancing sensitivity to immunotherapy. In conclusion, this thesis study has revealed important findings regarding the regulation of immune checkpoint molecules through small molecules targeting immune escape mechanisms in pancreatic cancer, thus paving the way for the development of next-generation therapeutic strategies for innovative and targeted combination therapies aimed at reprogramming the immunotherapy-resistant tumor microenvironment.