Abstract PO-104: Activation of WNT signaling in CD4+ T cells promotes immune suppression in pancreatic cancer

Abstract

Abstract WNT ligand expression and activation of the WNT signaling have been associated with pancreatic ductal adenocarcinoma (PDA). Using a mouse model that recapitulates the stepwise progression of PDA, we previously showed that epithelial WNT signaling is required for PDA initiation and progression. Through single cell RNA sequencing, we discovered that, in addition to epithelial cells, infiltrating immune cells and in particular T cells express the WNT signaling machinery, including receptors, downstream effectors and target genes. In particular, T cells express high levels of Tcf7, encoding the transcription factor TCF1. TCF1 is important for T cell development, but its role in adult T cells and specifically in the setting of pancreatic cancer remained unknown. To address this, we generated mice that allow deletion of Tcf7 specifically in CD4+ T cells in an inducible manner. We then implanted orthotopic syngeneic tumors in control mice or in mice lacking Tcf7 in CD4+ T cells, and observed reduced tumor growth in the latter. Analysis of the tumors revealed an increase in apoptotic cells; while the prevalence of infiltrating T cells did not change, we observed an increase in cytotoxic marker expression, such as Granzyme B, consistent with increased T cell activation. We observed decreased regulatory T cells, possibly indicating less immune suppression. However, we also observed a compensatory infiltration of increased granulocytic myeloid derived suppressor cells. Deletion of Tcf7 in CD4+ T cells also re-polarized the immunosuppressive macrophages into pro-inflammatory macrophages, and alterations of inflammatory cytokines secreted by cancer associated fibroblasts. Taken together, this study reveals an important role of WNT signaling in CD4+ T cells in the PDA microenvironment. We are currently evaluating ways to exploit changes in the immune microenvironment upon inactivation of Tcf7 in CD4+ T cells in combination therapy approaches. Citation Format: Wenting Du, Rosa E. Menjivar, Katelyn Donahue, Ashley Velez-Delgado, Marina Pasca di Magliano. Activation of WNT signaling in CD4+ T cells promotes immune suppression in pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-104.