Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 220, Issue 1, Pages -Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20220503
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Funding
- National Institutes of Health (NIH)/National Cancer Institute (NCI) [R0-CA271510, R01-CA264843, R01-CA151588, U01-CA224145]
- University of Michigan Training Program in Organogenesis (NIH) [T32-HD007505]
- University of Michigan Rackham Merit Fellowship [NIH T32-GM007315]
- Center for Organogenesis Training Program [NIH T32-HD007505]
- NCI [R50-CA232985]
- University of Michigan Cancer Biology Training Grant [NIH T32-CA009676, NCI F31-CA265085-01A1]
- University of Michigan Immunology Training Grant [NIH T32-AI007413]
- University of Michigan Rackham Merit Fellowship, Cellular Biotechnology Training Grant [NIH T32-GM008353, NCI F31-CA247037]
- American College of Gastroenterology Junior Faculty Development Award
- VA Career Development Award Biomedical Laboratory Research & Development Service
- American Cancer Society Clinician Scientist Development Grant [18-167-01]
- Rogel Cancer Center Immunology Core
- Microscopy Core at the University of Michigan
- Indiana University Simon Cancer Center Flow Cytometry Core
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The study found that targeting the WNT signaling pathway and PD-L1 in pancreatic cancer can reduce tumor growth by influencing the immune microenvironment.
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.
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