Disruption of fibroblast MYD88 signaling promotes antitumor immunity in pancreatic ductal adenocarcinoma
Pancreatic ductal adenocarcinoma (PDAC) continues to carry a dismal prognosis. The disease is characterized by a uniquely dense fibrotic matrix generated by cancer-associated fibroblasts (CAFs). We have previously demonstrated that fibroblast-driven chronic inflammation suppresses T cell function through a myeloid differentiation primary response protein 88 (MYD88)-dependent mechanism. While extensively studied in myeloid cells, the role of MYD88 signaling in CAFs and its effects on PDAC remain poorly understood. In this study, we identify a MYD88-driven inflammatory CAF population in PDAC using a combination of bulk, single-cell, and spatial transcriptomic studies. Using an innovative collagen gel implantation model, we demonstrate that loss of MYD88 in CAFs enhances T cell infiltration and suppresses tumor growth. Combining MYD88 inhibition with immune checkpoint blockade significantly reduces tumor size and enhances antitumor immune responses, underscoring its potential as a therapeutic target in PDAC.
Authors
- Khristian E Bauer-Rowe
- Byrne Lee (ORCID: https://orcid.org/0000-0002-1950-0262)
- Daniel Delitto (ORCID: https://orcid.org/0000-0002-2838-5841)
- Ovijit Chaudhuri (ORCID: https://orcid.org/0000-0002-9287-3401)
- Gregory W. Charville (ORCID: https://orcid.org/0000-0002-2774-2704)
- Deshka S. Foster (ORCID: https://orcid.org/0000-0001-8372-4722)
- Heather E. Talbott (ORCID: https://orcid.org/0000-0003-0250-925X)
- Amanda Kirane (ORCID: https://orcid.org/0000-0003-3489-1182)
- Jason L. Guo (ORCID: https://orcid.org/0000-0002-7264-2614)
- Monica M. Dua (ORCID: https://orcid.org/0000-0002-6187-8517)
- Rosyli F. Reveron‐Thornton (ORCID: https://orcid.org/0000-0002-4943-581X)
- Antonio Tomasso (ORCID: https://orcid.org/0000-0003-2869-1969)
- Derrick C. Wan (ORCID: https://orcid.org/0000-0003-4666-1683)
- Amanda Gonçalves (ORCID: https://orcid.org/0000-0003-2748-3033)
- Jeffrey A. Norton (ORCID: https://orcid.org/0000-0003-4762-9466)
- John Lu (ORCID: https://orcid.org/0000-0002-3972-8854)
- Lipika Goyal (ORCID: https://orcid.org/0000-0002-9777-6221)
- George A. Poultsides (ORCID: https://orcid.org/0000-0002-7584-0405)
- Biren Reddy (ORCID: https://orcid.org/0000-0001-8891-3610)
- Ping Xie (ORCID: https://orcid.org/0000-0002-7338-3730)
- Andrea E. Delitto
- Maria Korah
- Brendan C. Visser (ORCID: https://orcid.org/0000-0002-4874-1874)
- Kenneth W. Yip (ORCID: https://orcid.org/0000-0001-6703-5425)
- Chuner Guo (ORCID: https://orcid.org/0000-0003-4202-9285)
- James Paul Agolia (ORCID: https://orcid.org/0000-0001-5357-3871)
- M R Mohammadi Fallah (ORCID: https://orcid.org/0009-0004-2114-5169)
- Benjamin Pham
- Renceh A. B. Flojo
- Angela D Tabora
Institutions
- Stanford Medicine (US)
- Stanford University (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-09-25
- DOI
- https://doi.org/10.1016/j.celrep.2025.116347
- Citations
- 1
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 0.81