Abstract C046: Enhancing T cell infiltration and migration in the pancreatic tumor microenvironment

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers, with a five-year survival rate only increasing from 6% to 12% in the last decade, indicating an urgent need for new therapeutic approaches. In recent years, immunotherapies like chimeric antigen receptor (CAR)-T cell therapy, have demonstrated promising therapeutic results in treating several hematological malignancies. However, the success has been limited in treating solid tumors, especially for PDAC. Factors contributing to this poor response include poor immunogenicity, highly heterogeneous and robust fibrotic and immunosuppressive tumor microenvironments (TMEs). Here, we used state-of-the-art imaging coupled with quantitative analysis to study dynamic T cell migration behavior in organotypic pancreatic tumor slices harvested from genetically engineered KPC mice. Our data showed that T cell speed and overall motility are both significantly lower in stroma-rich region PDA regions than observations in carcinoma cell-rich regions, where collagen fibers are loosely connected. Next, we utilized stroma-targeted approaches to deplete collagen and hyaluronan, the most abundant ECM components in the TME, to remove the biophysical barriers for effective immune therapy. Indeed, preliminary data demonstrated improved T cell infiltration and migration in the tumor slices in the STT-treated groups compared to the control groups. The observation is also confirmed with a therapeutic cell line generated with mesothelin-specific T cell receptors. Furthermore, we utilized genome engineering to generate CD8+ T cells that more effectively migrate in fibrous TMEs. Time-lapse imaging of the engineered T cells shows an increased 3D migration compared to control groups. Taken together, our data suggest that engineered T cell approaches in combination with stromal targeted therapies to diminish stromal ECM content have the potential to improve immunotherapy by allowing effector T cells to sample the tumor volume more effectively. Citation Format: Hongrong Zhang, Guhan Qian, Zhongming Chen, Branden Moriarity, Ingunn Stromnes, David Odde, Paolo Provenzano. Enhancing T cell infiltration and migration in the pancreatic tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C046.