| First Author | Du W | Year | 2023 |
| Journal | J Exp Med | Volume | 220 |
| Issue | 1 | PubMed ID | 36239683 |
| Mgi Jnum | J:330168 | Mgi Id | MGI:7366875 |
| Doi | 10.1084/jem.20220503 | Citation | Du W, et al. (2023) WNT signaling in the tumor microenvironment promotes immunosuppression in murine pancreatic cancer. J Exp Med 220(1):e20220503 |
| abstractText | Pancreatic ductal adenocarcinoma (PDA) is associated with activation of WNT signaling. Whether this signaling pathway regulates the tumor microenvironment has remained unexplored. Through single-cell RNA sequencing of human pancreatic cancer, we discovered that tumor-infiltrating CD4+ T cells express TCF7, encoding for the transcription factor TCF1. We conditionally inactivated Tcf7 in CD4 expressing T cells in a mouse model of pancreatic cancer and observed changes in the tumor immune microenvironment, including more CD8+ T cells and fewer regulatory T cells, but also compensatory upregulation of PD-L1. We then used a clinically available inhibitor of Porcupine, a key component of WNT signaling, and observed similar reprogramming of the immune response. WNT signaling inhibition has limited therapeutic window due to toxicity, and PD-L1 blockade has been ineffective in PDA. Here, we show that combination targeting reduces pancreatic cancer growth in an experimental model and might benefit the treatment of pancreatic cancer. |
