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

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.