Dissecting the regulatory network of immune cells in the immunosuppressive tumor microenvironment

The immunosuppressive tumor microenvironment (ITM) is one of the main obstacles that limit the mounting of effective immune responses against tumors. ITM of pancreatic cancer plays a major role in the poor response of patients to immunotherapy and it includes the expression of immunosuppressive cytokines and desmoplastic tumor microenvironment (TME).

We investigate how pancreatic cancer develops, and explore how the epithelial cell change over time, how the different cell-type in the TME interact with each other, and how ITM is formed. We are using mice models that support the expression of constitutively active Kras in the acinar cells and we found that an immunosuppressive environment evolves in an early pre-malignant stage. We also profiled the effect of pancreatic injury on the accumulation of immune cells in the tissue and how the inflammatory process enhances high-grade lesion formation.

We use this information and develop a new method that supports the finding of genetic perturbation in immune cells to allow immune cells resistance to the suppressive signal. Adoptive cell transfer of perturbed immune cells results in the mounting of immune response that restricts tumor growth.

Together, our strategy supports the finding of immune cell perturbation that protects the immune system from suppressive signals and limits cancer development.