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

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is considered an immunologically cold cancer type. This perception is due to its rapid progression, strong presence of immunosuppressive cells and lack of response to current immunotherapies. However, we and others have shown that many patient PDAC tumors contain robust lymphocyte infiltration, aggregated in the form of tertiary lymphoid structures (TLS). The presence of TLS in PDAC is prognostic for long-term survival and in other cancer types, predictive of response to immunotherapy. Despite the clinical benefit to generating TLS in tumors, why they form in some PDAC patients but not others, remains unknown. The desmoplastic stroma in PDAC contributes to defective anti-tumor immunity largely due to myofibroblastic cancer associated fibroblasts (myCAF) induced by transforming growth factor-beta (TGF). Other groups have demonstrated that mesenchymal cell phenotypes with lymphoid tissue organizing properties regulate TLS formation in tumors. In order to restore effective anti-tumor immunity for PDAC patients, CAF phenotypes must be reprogrammed to support rather than restrict intratumoral immune activity. Using a lymphotoxin beta receptor (LTBR) agonist we observed induction of TLS-like aggregates in some murine PDAC tumor models, but not others. The CAF phenotypes of TLS-resistant models were predominantly myCAF while the TLS-permissive models were enriched for a VCAM1+ICAM1+ reticular-CAF (rCAF) subset. Induction of myCAF differentiation in vitro with TGF1 silenced LTBR/TNFR mediated upregulation of rCAF chemokine expression and attenuated B and T cell migration towards fibroblasts. Therapeutic TGFR1 inhibition ameliorated these effects thereby allowing LTBR agonism to repolarize rCAF phenotypic programming associated with improved lymphocyte recruitment and T cell-dependent tumor control. In patient PDAC tumors, rCAF resided next to TLS while myCAF were distally located. These data indicate that the myCAF-regulated PDAC stroma antagonizes acquisition of rCAF subsets critical for TLS formation but can be therapeutically remodeled to promote beneficial immune responses in immunosuppressive PDAC tumors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE322767 | GEO | 2026/03/04

REPOSITORIES: GEO