Cure the Incurable: Supercharged Immune Cells to Fight Disease

Project Overview

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer with very few treatment options. The 5-year survival rate for PDAC is 10% following diagnosis. While leveraging the immune system has revolutionized treatment options for many types of cancer including leukemia, lymphoma, melanoma and lung cancer, progress has been significantly limited in difficult to treat tumors, like PDAC, that lack immune infiltration into the tumor microenvironment. Cadherin 11 (Cdh11), a cell-to-cell adhesion molecule, has been suggested to promote tumor growth and immunosuppression in PDAC, and Cdh11 inhibition significantly extended survival in mice with PDAC. However, the mechanisms by which Cdh11 deficiency alters PDAC tumor microenvironment have yet to be fully elucidated. Understanding how Cdh11 promotes an immunosuppressive tumor microenvironment in PDAC will provide invaluable insights into developing new clinical approaches for effective eradication of cancer cells, in solid tumors that are classically immunodeficient. In this study, we investigated the role of Cdh11 in PDAC using a mouse model of PDAC. Our data suggests that Cdh11 deficiency significantly alters the molecular profile of fibroblasts in the tumor microenvironment and contributes to the downregulation of many inflammatory and immune-modulatory cytokines, leading to an increase in anti-tumor immunity and enhanced survival. Findings from this study expand our knowledge of the role of Cdh11 in tumor microenvironment and could open new avenues for developing new and improved therapeutic approaches for difficult to treat cancers such as PDAC.

Mission Impact

Our research supported and leveraged Lawrence Livermore National Laboratory's Core Competencies in ‘bioscience and bioengineering' to advance human health. We also leveraged Livermore's capabilities in ‘high-performance computing, simulation and data science' to advance the field of ‘predictive biology—enabling a new, precision approach to data- and simulation-driven threat characterization, diagnosis, and intervention development.' This study significantly improved our fundamental understanding of tumor microenvironment and identified several potential therapeutic targets for PDAC, a difficult to treat cancer with high mortality rate.

Publications, Presentations, and Patents

K. A. Martin, A. Sebastian et. al, "Loss of cadherin 11 in pancreatic cancer induces altered immune cell infiltration" (Poster Presentation, American Association for Cancer Research Annual Meeting 2022, Philadelphia PA, April 8-13, 2022). LLNL-POST-820889.