2. Academic Validation
  3. Myofibroblast programming blocks differentiation of TLS-organizing fibroblastic reticular cells in pancreatic cancer

Myofibroblast programming blocks differentiation of TLS-organizing fibroblastic reticular cells in pancreatic cancer

  • Cancer Cell. 2026 Mar 26:S1535-6108(26)00156-X. doi: 10.1016/j.ccell.2026.03.004.
Elijah Kirschstein 1,  Olivia Harder 1,  Jordan Krull 2,  Madison Sikorski 1,  Shrijan Khanal 1,  Morgan Mack 1,  Carl F Ware 3,  Elizabeth Evans 4,  Michael J Gough 5,  Qin Ma 2,  Wei Chen 6,  Kristina H Young 7,  Andrew J Gunderson 8
Affiliations

Affiliations

  • 1 Department of Surgery, Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
  • 2 Department of Biomedical Informatics, The Ohio State University College of Medicine, Columbus, OH 43210, USA.
  • 3 Sanford Burnham Preybus Medical Discovery Institute, La Jolla, CA 92037, USA.
  • 4 Vaccinex Inc., Rochester, NY 14620, USA.
  • 5 Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR 97213, USA.
  • 6 Department of Pathology, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
  • 7 Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR 97213, USA; Radiation Oncology Division, The Oregon Clinic, Portland, OR 97231, USA.
  • 8 Department of Surgery, Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA. Electronic address: andrew.gunderson@osumc.edu.
PMID: 41895277 DOI: 10.1016/j.ccell.2026.03.004
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is strongly resistant to immunotherapy. However, recent evidence shows that some PDAC tumors contain tertiary lymphoid structures (TLSs) associated with improved survival. Why TLS forms in some tumors but not Others remains elusive. Using a lymphotoxin beta receptor (LTBR) agonist, we observe the induction of TLS-aggregates in some murine PDAC tumor models but not Others. The phenotypes of cancer-associated fibroblasts (CAFs) in TLS-resistant models are myofibroblastic (myCAF), whereas TLS-permissive models are enriched with reticular-CAF (rCAF) subsets. Differentiation into myCAF blocks the LTBR-mediated upregulation of chemokines and lymphocyte migration toward fibroblasts. Inhibiting the transforming growth factor β (TGFβ) receptor, combined with LTBR agonism, promotes TLS formation and T cell-dependent tumor control. In patient tumors, rCAF are proximal to TLS, while myCAF are distally located. These data indicate that myCAF represses rCAF programming critical for TLS formation but can be therapeutically remodeled to promote immune control of PDAC tumors.

Keywords

cancer associated fibroblasts; pancreatic cancer; tertiary lymphoid structures; tumor immunity.

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