WNT signaling in the tumor microenvironment promotes immunosuppression in murine pancreatic cancer

J Exp Med. 2023 Jan 2;220(1):e20220503. doi: 10.1084/jem.20220503. Epub 2022 Oct 14.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • B7-H1 Antigen / genetics
  • CD8-Positive T-Lymphocytes
  • Carcinoma, Pancreatic Ductal* / metabolism
  • Humans
  • Immunosuppression Therapy
  • Lymphocytes, Tumor-Infiltrating
  • Mice
  • Pancreatic Neoplasms* / pathology
  • Transcription Factors / metabolism
  • Tumor Microenvironment
  • Wnt Signaling Pathway


  • B7-H1 Antigen
  • Transcription Factors