Mechanisms of pancreatic cancer cell resistance to T cell-mediated cytotoxicity

• Applicant: Privatdozentin Dr. Yuan-Na Lin, Ph.D.
• Subject Area: Gastroenterology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 522873233

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with limited treatment options and mostly resistant to immunotherapy. Despite a high abundance of T cells in its microenvironment, their ability in executing a cytotoxic response is thought to be diminished by an immunosuppressive microenvironment as well as cancer cell-autonomous resistance mechanisms. Pancreatic cancer cell-autonomous resistance mechanisms intersect with known oncogenic pathways and understanding their interplay is essential to uncover targetable genes and associated pathways that modulate T cell-responses. Under three distinct aims we will identify genes and pathways that control cancer cell resistance and sensitivity to T cell-mediated killing. We will use PDAC clonal cell lines from KPC (LSL-KrasG12D/LSL-TP53R172H/P48-cre) tumors either resistant or sensitive to killing by in vivo tumor-educated T cells in co-culture. Based on our previous comparative transcriptomic analysis of sensitive and resistant PDAC cells, we will first focus on the most promising gene candidates and differentially activated pathways, which potentially modulate a T cell response against cancer cells (Aim 1). In addition, we will perform kinome-wide shRNA library screens on PDAC cells to identify kinases that are rate-limiting for the resistant phenotype in sensitive cancer cells (Aim 2) and control the sensitive phenotype in resistant cancer cells (Aim 3). The identified candidate genes will be validated and characterized using in vitro and in vivo assays. The clinical significance will be assessed by correlative analysis using pluripotent stem cell (PSCs)-derived pancreatic duct-like organoids (PDLOs) and patient-derived organoids (PDOs) as human validation platforms. Identification and characterization of novel genes and pathways in regulating T cell response could provide insights into immunomodulatory actions of targeted anticancer drugs and how to apply kinase inhibitors to sensitize pancreatic cancer cells towards T cell-mediated cytotoxicity.

• DFG Programme: Research Grants