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A Mouse Model to Investigate the Role of Cancer-Associated Fibroblasts in Tumor Growth
Published on: December 22, 2020
Myofibroblast programming blocks differentiation of TLS-organizing fibroblastic reticular cells in pancreatic cancer
Elijah Kirschstein1, Olivia Harder1, Jordan Krull2
1Department 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.
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.
Insights
Pancreatic cancer immunotherapy resistance can be overcome by promoting tertiary lymphoid structures (TLS). Myofibroblastic cancer-associated fibroblasts (myCAFs) block TLS formation, but TGFβ inhibition can remodel them to enhance anti-tumor immunity.
Area of Science:
- Immunology
- Oncology
- Cancer Biology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) exhibits resistance to immunotherapy.
- Tertiary lymphoid structures (TLS) in PDAC tumors correlate with improved patient survival.
- The mechanisms governing TLS formation in PDAC remain unclear.
Purpose of the Study:
- To investigate the role of cancer-associated fibroblasts (CAFs) in TLS formation within PDAC.
- To identify therapeutic strategies for enhancing TLS formation and anti-tumor immunity in PDAC.
Main Methods:
- Utilized a lymphotoxin beta receptor (LTBR) agonist in murine PDAC models.
- Characterized CAF subsets (myofibroblastic - myCAF, reticular - rCAF) in TLS-permissive and TLS-resistant tumors.
- Investigated the impact of TGFβ receptor inhibition combined with LTBR agonism on TLS formation and T cell infiltration.
- Analyzed CAF localization relative to TLS in human PDAC patient tumors.
Main Results:
- LTBR agonism induced TLS in a subset of murine PDAC models.
- TLS-resistant models were enriched with myCAFs, while TLS-permissive models had more rCAFs.
- myCAFs inhibited LTBR-mediated chemokine upregulation and lymphocyte migration.
- Combined TGFβ receptor inhibition and LTBR agonism promoted TLS formation and T cell-dependent tumor control.
- In human PDAC, rCAFs were located near TLS, whereas myCAFs were found distally.
Conclusions:
- myCAFs suppress rCAF programming essential for TLS formation.
- Therapeutic remodeling of myCAFs can enhance TLS formation and anti-tumor immune responses in PDAC.
- Targeting the TGFβ pathway alongside LTBR agonism represents a promising strategy for PDAC immunotherapy.
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