While it is appreciated that host immunity plays a critical role in regulating tumorigenesis, the mechanisms behind immune response evasion in Kras-driven pancreatic cancer are poorly understood. For example, while T cells with specificities against tumor antigens have been found in human pancreatic ductal adenocarcinoma, it is not clear if antigen-dependent pathways would be utilized as the main driving forces in productive anti-tumor immunity. Meanwhile, this information is crucial for the development of T- and dendritic-cell based immunotherapies. Similarly, while systemic immune changes have been documented in patients with metastatic pancreatic cancer, our understanding of the role of the immune system in the process of pancreatic cancer metastasis is scant.
Our current research aims to elucidate the cellular and molecular mechanisms of immune cell co-option by cancer cells, and to determine the significance of this crosstalk in tumor initiation and progression to metastatic disease. To achieve this, we use genetically engineered spontaneous and transplant-based mouse models of pancreatic cancer that feature activation of oncogenic Kras and mutations in tumor suppressor p53. These mouse models recapitulate key features of human pancreatic adenocarcinomas characterized by extensive remodeling of the surrounding microenvironment complete with pronounced influx of immune cells that shape the inflammatory and immunosuppressive pro-tumorigenic milieu. These pathological features of pancreatic ductal adenocarcinoma highlight the potential clinical significance of investigational efforts into mechanisms of immunomodulation in pancreatic cancer.
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