Liberating T-Cell Mediated Immunity to Pancreatic Cancer Using Theoretical Biophysics Analysis

University Of Pennsylvania, Philadelphia PA

Investigators

Abstract

This award is part of the NSF effort to promote significant advances in the fundamental understanding of cancer biology made possible through multidisciplinary research that involves experts in theoretical physics, applied mathematics, and computer science. Pancreatic cancer is a common and increasing cause of cancer death. While innovative strategies involving the immune system have brought progress in the treatment of many cancers, these strategies have to date been ineffective in pancreatic cancer. These tumors release immunosuppressive molecules and act as a physical barrier causing reduced immune cell infiltration and activation. Recently it was shown that large doses of Vitamin D result in reduced immunosuppression and increased immune cell infiltration in tumors, setting the stage for an effective immune cell attack on pancreatic cancer. The heart of this project is the use of theoretical modeling and statistical understanding of immune cell repertoires to design successful immune system attack on the cancer. In this project a team of theoretical physicists and cancer researchers will work together to design quantitative strategies based on the immune system to attack pancreatic cancer. Novel theoretical and experimental tools will be used to characterize the immunological environment of pancreatic cancer tumors and the detailed understanding of the immune cell response dynamics will be used to develop innovative interventions. The project will focus on quantifying the poorly understood immune environment of pancreatic ductal adenocarcinoma. T cell receptor sequence repertoires, the cancer exome, and RNA expression will be obtained from tumor tissue of patients treated with neoadjuvant chemotherapy plus a high dose vitamin D. Whether the T cells infiltrating patient tumors represent unique or oligoclonal cell populations will be determined. Parallel studies will systematically assess cytokine expression and the expression of checkpoint proteins, as well as the presence of immunoregulatory cell populations. Exome sequencing analysis using theoretical physics and mathematical approaches will be used to gain initial insight into potential neo-antigens expressed by tumors. The quantitative models and analysis tools will be used to develop integrated platform for attacking this cancer. This proposal is cofunded by the Physics of Living Systems Program in the Physics Division and the Systems and Synthetic Biology Program in the Molecular and Cellular Biosciences Division.