The Contribution of Cancer-Associated Fibroblasts to T Cell Infiltration in Lung Adenocarcinoma
Navpreet Tung1, Léa Karpf1, Samuel Rose1, John Grout1, Miriam Merad1 and Hélène Salmon1 1Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
Lung cancer is the leading cause of cancer-related deaths worldwide. The preferential retention of T cells to the peritumoral stroma observed in the majority of lung cancer patients has been shown to limit anti-tumor T cell function and the success of T cell-based immunotherapies; it is therefore crucial to understand the mechanisms regulating T cell exclusion. While the role of fibroblasts in shaping lymphocyte compartmentalization in secondary lymphoid organs is well established, little is known about fibroblast-T cell crosstalk within the tumor microenvironment. Our group has previously reported that matrix fibers in the stroma of human lung tumors form a dense physical barrier around tumor islets that restricts T cell contact with tumor cells. In mouse tumor models, we have observed progressive T cell exclusion during tumor development that correlates with changes in cancer-associated fibroblast (CAF) phenotype. Based on these results, we hypothesize that CAFs play a key role in regulating T cell distribution at the tumor site and that targeting CAFs may enhance T cell infiltration into the tumor mass. Utilizing tumor graft and transgenic mouse models of KrasG12D/p53null lung adenocarcinoma, we have observed that local delivery of the viral mimetic, polyI:C, induces sustained T cell entry into tumor islets and that polyI:C has a direct effect on fibroblasts to facilitate T cell infiltration. RNA-sequencing of CAFs from lung tumors treated with polyI:C led us to identify candidate genes associated with T cell infiltration, including cytokines, adhesion molecules, and extracellular matrix molecules. We are now using CRISPR-Cas9 gene editing to knockout these candidate genes in lung fibroblasts and assess their role in a 3D tumor-fibroblast-T cell spheroid system that we recently developed in which T cell motility can be monitored through real-time imaging. Collectively, these data aim to identify novel stromal targets that, when combined with immunotherapy, will further enhance T cell infiltration and anti-tumor responses.
Credits: None available.
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